1 s2.0 S1673852721000436 Main

Journal of Genetics and Genomics xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Genetics and Genomics

Journal homepage: www.journals.elsevier.com/journal-of-genetics-
and-genomics/
Review
Interplay between genome organization and epigenomic alterations of

pericentromeric DNA in cancer
Subhadip Kundu a, M.D. Ray b, Ashok Sharma a, *
a
Laboratory of Chromatin and Cancer Epigenetics, Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029,
India
b
Department of Surgical Oncology, IRCH, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
a r t i c l e i n f o a b s t r a c t
Article history: In eukaryotic genome biology, the genomic organization inside the three-dimensional (3D) nucleus is
Received 6 September 2020 highly complex, and whether this organization governs gene expression is poorly understood. Nuclear
Received in revised form lamina (NL) is a filamentous meshwork of proteins present at the lining of inner nuclear membrane that
7 February 2021
serves as an anchoring platform for genome organization. Large chromatin domains termed as lamina-
Accepted 20 February 2021
Available online xxx
associated domains (LADs), play a major role in silencing genes at the nuclear periphery. The interaction
of the NL and genome is dynamic and stochastic. Furthermore, many genes change their positions during
developmental processes or under disease conditions such as cancer to activate certain sorts of genes
Keywords:
LADs
and/or silence others. Pericentromeric heterochromatin (PCH) is mostly in the silenced region within the
Pericentromere genome, which localizes at the nuclear periphery. Studies show that several genes located at the PCH are
Heterochromatin aberrantly expressed in cancer. The interesting question is that despite being localized in the pericen-
Gene regulation tromeric region, how these genes still manage to overcome pericentromeric repression. Although
Epigenetics epigenetic mechanisms control the expression of the pericentromeric region, recent studies about
Cancer genome organization and genome-nuclear lamina interaction have shed light on a new aspect of peri-
Genome organization centromeric gene regulation through a complex and coordinated interplay between epigenomic
remodeling and genomic organization in cancer.
Copyright © 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and
Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.
Introduction supporting strong epigenetic regulation to maintain cellular iden-

tity. However, oncogenic adaptations in cells provide epigenetic
Genomic instability is a hallmark of cancer (Hanahan et al., plasticity which leads to the expression of stem cell marks and si-
2011). Cancer cells present an analogous genome architecture, lent heterochromatic loci conferring strong links between game-
where the cell differentiation program is highly unstable and togenesis and cancer (Fanelli et al., 2008; Yamada et al., 2013).
plastic at both the genetic and epigenetic levels. Cancer cells pre- The role of centromeres in maintaining chromosomal structure
sent mutations and genomic rearrangements at the genetic level is well established. Centromeric regions show frequent instability
that often develop modified gene products of already-expressed during various pathological conditions such as Robertsonian
genes and several new fusion gene transcripts such as the Phila- translocation (Mudge and Jackson, 2005). Interestingly, this insta-
delphia chromosome (Kang et al., 2016). Cancer cells show altered bility is also extensively expanded to the pericentromeric regions
genomic architecture inside the nucleus with new transcriptional on all chromosomes. Pericentromeric DNA has been defined as a
programs in specific cell types to support unregulated neoplastic chromosomal region distal to the a-satellite repeat and is extended
growth (Chakravarthi et al., 2016). Most tumor cells maintain their up to the first cytogenetic Giemsa-stained band on either side of the
tissue-specific epigenetic signatures as a cellular identity that centromere, thereby separating the centromeric heterochromatin
makes their identification possible even at metastatic sites, thus and euchromatin (Eichler, 1998; Brun et al., 2003). The pericen-
tromeric locus plays a structural role in maintaining the centro-
mere integrity by regulating the centromeric cohesion at mitotic
* Corresponding author.
division (Alonso et al., 2010). Several studies have shown that
E-mail address: [email protected] (A. Sharma). alteration of the pericentromeric heterochromatin (PCH) may be a
https://doi.org/10.1016/j.jgg.2021.02.004
1673-8527/Copyright © 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and
Science Press. All rights reserved.
Please cite this article as: S. Kundu, M.D. Ray and A. Sharma, Interplay between genome organization and epigenomic alterations of
pericentromeric DNA in cancer, Journal of Genetics and Genomics, https://doi.org/10.1016/j.jgg.2021.02.004
S. Kundu, M.D. Ray and A. Sharma Journal of Genetics and Genomics xxx (xxxx) xxx
key contributor to centromeric instability, which conversely can be evolutionary analysis of pericentromeric sequences have shown
a novel therapeutic target for epigenetic therapy in aggressive that these regions have been subjected to recent duplication events
cancers (Slee et al., 2012). Although recently published studies have for both interchromosomal duplications and intrachromosomal
provided clues for the important functions of the pericentromeric duplications, and several genes are undergoing rapid evolution in
gene, the molecular mechanism underlying the silent pericentro- hominid lineages (Bailey et al., 2001, 2002; Fortna et al., 2004; Hall
meric gene activation is poorly explored. Furthermore, nuclear ar- et al., 2006). Pericentromeric genes are highly enriched for trans-
chitecture and genomic organization inside the 3D nucleus have poson insertions, which are well-documented factors contributing
been shown to play a crucial role in gene expression during cellular to genome expansion and evolution in plants. As transposable el-
differentiation (Peric-Hupkes et al., 2010), senescence ements need to be checked for maintaining fertility, newly created
(Cruickshanks et al., 2013; Shah et al., 2013), and cancer (Berman gene transcripts arising from this locus, albeit less in number, un-
et al., 2012; Hon et al., 2012; Reddy et al., 2013). dergo strong natural selection. This process also imparts a powerful
Exploring nuclear topology-mediated gene regulation has role in primates’ evolutionary adaptations, and there are many
become a universal interest. Specifically, heterochromatin, which primate-specific genes at this locus in the human genome
usually lies at the nuclear periphery and associates with the NL, has (Guschanski et al., 2017).
been identified as a key player in repressing the expression of the Pericentromeres in animals contains extensive segmental du-
genes positioned in these regions. In metazoan nuclei, the NL, plications. Approximately one-third of human-specific segmental
composed of lamin proteins, is present at the lining of the inner duplications reside within pericentromeric regions. These paralo-
nuclear membrane. Lamin proteins are fibrous proteins composed gous genes show differential tissue-specific expression in different
of type V intermediate filaments. All lamin proteins exhibit ho- organs, suggesting a differential contribution of paralogs to specific
mology in their amino acid sequence and form a coiled-coil struc- organ functions during vertebrate evolution (Guschanski et al.,
ture similar to other intermediate filaments, but they differ in 2017). In cancer, pericentromeric duplicated genes have been pri-
posttranslational modifications. Based on their structure, lamins marily included in the cancer-testis antigen (CTA) gene family
are grouped as A-type and B-type (Goldman et al., 2002; Shumaker because of their specific expression pattern. Pericentromeric gene
et al., 2003; Broers et al., 2006). The two splice variants of A-type expression in cancer has been primarily ignored because of
lamin, Lamin A/C, are coded by the LMNA gene. Lamin B1 and Lamin extensive sequence homology, as sequence similarities create dif-
B2, the two major B-type lamins, are coded by LMNB1 and LMNB2 ficulties in studying any specific paralog. Only recently high-
genes, respectively. throughput transcriptomic approaches have made the identifica-
Previously, electron microscopy-based studies showed a tight tion of locus-specific transcripts of pericentromeric genes possible.
apposition of the condensed chromatin layer adjacent to the NL
(Fawcett et al., 1966), which bestows a preliminary indication that Organization of the human pericentromere
some heterochromatin regions are positioned at the nuclear pe-
riphery. However, later, a DNA fluorescent in situ hybridization The eukaryotic genome shows a remarkable division into
(FISH) study revealed that certain specific heterochromatin regions functional chromatin compartments that are spatiotemporally ar-
that are transcriptionally repressed, preferentially localized at the ranged inside the nucleus and are clearly identifiable during
nuclear periphery and interact with the NL (Lancto ^ t et al., 2007). metaphase. The centromere invariably comprises repetitive DNA or
Subsequent studies based on genome-wide mapping of NL contact satellites, but the sequence diverges in different species and be-
sites by DNA adenine methyltransferase identification (Dam-ID) tween the same organisms. In humans, centromeres comprise re-
technology identified genomic regions that usually make close petitive alpha-satellite DNA clustered into large tandem arrays.
contact with the nuclear lamina. These regions, which are hetero- Because of these highly repetitive structures, centromere
chromatin in nature, are designated as LADs (Guelen et al., 2008). sequencing has been difficult for all DNA sequencing strategies. The
Heterochromatin is divided into two subgroups that differ in goals of initial contemplate of the Human Genome Project have
their composition, expression pattern, and location within the acknowledged that “the small proportion of highly repeated se-
nucleus. Constitutive heterochromatin (CH) is found at and around quences represented by the centromere and other CH regions of the
centromeres (centromeric and pericentromeric heterochromatin) genome” might not be included in the final reference assembly
and can form clusters of multiple chromosomes which remain (Collins et al., 1998). Distal to the alpha satellites and before the first
permanently repressed (Saksouk et al., 2015). Facultative hetero- Giemsa band, the pericentromere is situated, creating a boundary
chromatin (FH) is specific for a particular cell type and is found at between permanently repressed CH and actively transcribed
the NL (Peric-Hupkes et al., 2010; Meuleman et al., 2013). Both euchromatin. As a transition locus, pericentromeric DNA is associ-
forms of heterochromatin are silencing compartments. It was also ated with unique genetic and epigenetic signatures.
reported that DNA methylation is highly correlated with genome-
nuclear lamina interactions and hypomethylated regions often Dysregulation of the pericentromeric region in cancer
overlap with LADs (Berman et al., 2012). This review will discuss
the PCH organization, its involvement in cancer development, and Frequent gene mutations and chromosomal rearrangements are
how a complex interplay between the spatial organization of PCH two factors that drive genomic instability, which can ultimately
and epigenome remodeling is involved in controlling pericentro- lead to the development of cancer (Hanahan and Weinberg, 2011).
meric gene regulation in cancer. Principally, three types of genomic instability have been defined:
chromosome instability, microsatellite instability, and base-pair
Insights into pericentromeric heterochromatin mutation. Chromosome instability can be attributed to variation
in the number of chromosomes resulted from improper segrega-
PCH consists mainly of tandem repeats with a few genes tion of chromosomes during the mitotic phase and by chromo-
compared with FH, which contains repressed genes that become somal rearrangement. Studies have provided important clues that
activated during embryonic development. While rich in transpos- the pericentromeric region of the chromosome 1q12 region un-
able elements, pericentromeric DNA provides a prime locus for dergoes chromosomal rearrangement and amplification that leads
genomic rearrangements and gene evolution and is, therefore, a to the development of cancer and its progression, and these pro-
‘hotspot’ for genome evolution (Hall et al., 2006). Several cesses are driven by epigenetic mechanisms (Traynor et al., 2019).
2
The chromosome 1q12 arm contains a mega-base size stretch of Epigenetic switching at pericentromeric DNA in cancer
PCH (SatII and SatIII repeat sequences), which is considered the
largest among the entire genome (Gjerstorff, 2020). This region is Epigenetic regulation by chromatin-modifying enzymes play
often rearranged and dysregulated in different types of cancers, crucial roles in maintaining nuclear architecture, chromosome
including solid tumors and hematopoietic malignancies (Mertens dynamics, gene expression, and meiotic recombination. PCH in
et al., 1997). For example, chromosomal translocation and, some- animal cells underlies distinct genetic and epigenetic signatures.
times, deletion of the chromosome 1q pericentromeric region are The heterochromatic regions are cytologically condensed during
involved in breast cancer tumorigenesis (Pandis et al., 1995). On the interphase and characteristically enriched with repetitive se-
other hand, nearly 25% of the gain in copy number of the 1q peri- quences and transposable elements (Fransz and De Jong, 2011). The
centromeric region is associated with primary cutaneous mela- genetic composition of PCH includes two types of sequences:
noma (Bastian et al., 1998). Studies have also reported a gain in copy various noncoding DNA sequences (retrotransposons, incomplete
number within the pericentromeric locus of the 1q12 chromosome gene fragments, and tandemly repeated satellite DNA) and a few
in hepatocellular carcinoma (Marchio et al., 1997; Wong et al., 1999; genes. Earlier sequencing strategies impose difficulties in
Chang et al., 2002). Furthermore, by performing a multicolor-FISH sequencing and mapping genetic and epigenetic features of peri-
experiment, the highest number of chromosomal breakages centromeric regions because of the high content of highly repeti-
within the chromosome 1q12 arm was found in lentigo malignant tive DNA and partial or full-length duplicated gene segments
melanoma (Dopp et al., 1997). Frequent amplification of 1q12 PCH present in different chromosomes. Advanced DNA sequencing ap-
was also observed in multiple myeloma by ‘jumping translocation’ proaches overcome this dilemma, and, hence, many full-length
where translocation of the 1q arm leads to an overall gain in copy gene transcripts from these loci have been reported in humans,
number, which also increases over time (Sawyer et al., 1998, 2019; including B-melanoma antigen (BAGE), transmembrane phospha-
Fournier et al., 2007). Sawyer et al. (1998) also reported that tase with tensin homology (TPTE), and prostate, placenta, ovary,
aberrant rearrangement of chromosome 1q by jumping trans- and testis expressed (POTE). The functions of repeat elements at
location in multiple myeloma is facilitated by decondensation of this locus have been studied widely, including the maintenance of
PCH. chromosome structure and gene expression regulation, which are
Although earlier studies have provided several important as- all altered during cancer. Several reports have explored the role and
pects that link pericentromeric aberrations and rearrangements underlying mechanism of long interspersed nuclear elements-
with cancer development, recent studies have shed light on a more 1 (LINE-1) retrotransposable elements in cancer, which encompass
interesting angle that links transcription of the silent pericentro- a major portion of pericentromeres.
meric region with cancer progression. While repressive epigenetic Pericentromeric DNA repression has been primarily attributed
mechanisms regulate the establishment of CH at the pericen- to established repressive epigenetic marks at this locus, including
tromere locus, disruption of this epigenetic control can cause histone marks, DNA methylation, nucleosome positioning, and
decompaction of PCH and lead to activation of transcription in this noncoding RNA. DNA methylation and histone modification coop-
otherwise silent region. Aberrant expression of SatII and SatIII re- erate to establish and maintain heterochromatin, including PCH
peats at the pericentromeric locus has been reported in several (Stancheva, 2005). Studies have shown that the disruption of one of
types of cancers, including pancreatic and epithelial cancers (Ting these marks leads to disruption of the other, which is explained by
et al., 2011; Smurova and De Wulf, 2018). Studies have shown the reinforcement mechanism (Stancheva, 2005; Du et al., 2015).
that human satellite II (HSATII) repeats, which are primarily local- However, the DNA methylation machinery seems to be a prime
ized at the pericentromeric region of chromosomes 2, 7, 10, 16, and regulator at the pericentromere locus. PCH is typical CH defined by
22, induce expression in colon cancer cells inside a xenograft model H3K9me3 (histone 3 lysine 9 trimethylation) and high levels of
or when colon cancer cells are grown in vitro under nonadherent DNA methylation (hypermethylation), whereas FH displays high
conditions (Bersani et al., 2015). The authors also showed that the H3K27me3 (histone 3 lysine 27 trimethylation) and DNA hypo-
HSATII transcript is further converted to a cDNA intermediate and methylation. CH is a gene-poor region, whereas FH is established at
generates a DNA-RNA hybrid, which leads to stable incorporation of genes that must be kept silent during development. These two
HSATII in the pericentromeric locus and contributes to overall copy states are mutually exclusive and show an explicit distinction in
number gain and repeats expansion. Pericentromeric HSATII repeat differentiated cells. During development, pericentromeric regions
expansion is a hallmark of colon cancer that is also attributed to a show plasticity between these two states, and the same happens in
lower survival rate (Bersani et al., 2015). In addition, some studies the case of cancer. Expression at this locus during gametogenesis is
have also focused on the function of pericentromeric transcripts in regulated by dynamic epigenetic alterations at different stages and
cancerous transformation. In one such study, Kishikawa et al. involves RNA Pol II recruitment and DICER (Khalil and Driscoll,
(2016) reported that overexpression of MajSAT RNA in pancreatic 2010). Pericentromeric gene expression in cancer involves signifi-
intraepithelial neoplasia, a premalignant condition, leads to its cant ‘epigenetic switching’, where constitutive PCH is converted
transformation into cancerous conditions by a mechanism, where into FH (De jardin, 2015). There is limited data on how this epige-
MajSAT RNA interacts with Y-box binding protein 1, a protein netic switching occurs, but reports suggest that during cancer,
involved in DNA damage repair, and blocks its translocation into the polycomb group proteins occupy PCH and provide a molecular sink
nucleus, thereby causing augmented genomic instability. jardin, 2015).
for epigenetic alterations (Saurin et al., 1998; De
Now the question arises, what leads to the activation of these
silent pericentromeric regions? Several studies have shown DNA methylation is the major regulator of pericentromeric gene
epigenetic mechanisms, such as DNA hypomethylation of satellite expression in cancer
repeats, as the key contributor to pericentromeric transcriptional
activation that leads to carcinogenesis (Narayan et al., 1998; Ehrlich, The expression of all DNA methyltransferases (DNMTs) has been
2009). In the upcoming section, we will discuss different epigenetic reported to be altered in cancer cells (Zhang and Xu, 2017). Reduced
mechanisms involved in heterochromatin establishment in the DNA methylation (hypomethylation) of repeat elements, including
pericentromeric region and how perturbation in epigenetic regu- LINE-1, is an important signature of many cancers associated with
lation can cause activation of pericentromeric transcription in altered DNA methyltransferase expression. LINE-1 methylation is
cancer. often used as a surrogate marker for global DNA methylation levels.
3
However, this terminology is imprecise or limited because gene- These patterns of histone modification are dynamic and change
specific methylation levels may be different. A loss of overall DNA during cell division.
methylation levels in cancer is often associated with high-grade One of the major repressive histone modifications at PCH is
tumors, and pericentromeric DNA rich in repeats is mostly hypo- H4K20me3, which is attained by sequential methylation by
methylated (Barger et al., 2018; Sharma et al., 2019). While the SUV420H1 or SUV420H2 enzymes (Sanders et al., 2004; Schotta
cause-and-effect relationship between altered DNA methylation in et al., 2008). Transcription of repetitive elements occurs by
cancer and other epigenetic signatures at PCH has not been eluci- H4K20me3 marks (Schotta et al., 2004, 2008; Fodor et al., 2010).
dated in detail, significant hypomethylation of the classical satellite SUV39H1, a histone methyltransferase among the five types pre-
repeat elements at the PCH is observed in ICF (immunodeficiency, sent in mammals, establishes the most prominent histone mark of
centromeric region instability, facial anomalies) syndrome, a rare euchromatin H3K9me2 and H3K9me3. While H3K9me2 is associ-
congenital disease associated with a mutation in a DNA methylated with several permissive marks, it is further converted to
transferase gene, DNMT3B (Jiang et al., 2005). ICF is a rare auto- H3K9me3, a stable chromatin modification that does not vary
somal recessive disorder characterized by severe significantly during the cell cycle. Most recently, studies have
immunodeficiency, craniofacial anomalies, and chromosome shown that these two H3K9me2/3 marks are functionally distinct.
instability (Ehrlich et al., 2008). This observation suggests that The Jumonji domain 2 (JMJD2) family of histone demethylases re-
pericentromeric expression is indeed DNA methylation-dependent verses trimethylation on H3K9 and antagonizes PCH formation
and that DNMT3B is a major regulator of DNA methylation at this (Whetstine et al., 2006). JMJD2, a member of a family of histone
locus (Walton et al., 2014). In addition, many pericentromeric genes demethylases, is responsible for removing H3K9 methylation.
reported to be expressed in cancer have also been shown to be Notably, JMJD2 overexpression has been reported in various can-
expressed in ICF without apparent chromatin changes (Brun et al., cers and has been implicated as a strong contributor to tumori-
2003). Morphological reprogramming of constitutive PCH has also genesis (Slee et al., 2012). Loss of H3K20me is common in cancer
been observed in drug-induced global DNA hypomethylation cells, yet the underlying mechanism remains undefined. Table 1
models, implying DNA methylation as an important regulator of lists different epigenetic marks present at the pericentromere
PCH architecture (Shvachko, 2008). Moreover, DNA hypo- which play crucial roles in PCH formation and gene regulation.
methylation is also reported at the chromosome 1q12 PCH region
and is associated with the development of many cancers (Ji et al., Pericentromeric genes as potential targets for cancer
1997; Wong et al., 2001; Tsuda et al., 2002). Hypomethylation of immunotherapy
the SatII pericentromeric region of chromosome 1 and chromo-
some 16 is observed in breast carcinoma (Tsuda et al., 2002). Recent advances in genome-wide transcriptome approaches
Furthermore, chromosome 1 hypomethylation at the 1q12 peri- have identified several pericentromeric genes highly expressed in
centromeric region is correlated with the copy number of the q arm germ cells as well as in most cancers (Mudge and Jackson, 2005;
in hepatocellular carcinoma (Wong et al., 2001). In addition, DNMT BrV Uckmann et al., 2018). These germline and cancer-specific
inhibitors have also been shown to play roles in the unfolding and expressions allow them to be included under the category of the
destabilization of SatII repeats in various cell types (Prada et al., cancer-testis/cancer germline (CT/CG) antigen gene family. CT/CG
2012; Brückmann et al., 2018). Hypomethylated HSATII DNA and antigens are activated in various tumors and have been shown to be
HSATII RNA are involved in sequestration of polycomb repressive recognized by autologous T cells (Van Der Bruggen et al., 1991). CG
complex 1 and methyl CpG binding protein 2 (MeCP2) into cancer- antigens are tumor-specific, thereby contemplated as prime can-
associated polycomb (CAP) and cancer-associated satellite tran- didates for cancer immunotherapy. CT antigen gene family consists
script (CAST) bodies, respectively, and aid in epigenome remodel- of two types of genes: CT-X antigens present on X chromosomes
ing and ultimately promote neoplastic growth (Hall et al., 2017). and non-CT-X antigens present on autosomes. However, compared
Taken together, these studies provide important indications that with similar germline genes located primarily on the X chromo-
DNA methylation dysregulation of PCH is closely associated with some, CT-X antigens have received little attention. X chromosome/
cancer development and linked with cancer-associated epigenome autosome-based division hides up the basic mechanism of their
remodeling. expression and their location-based heterochromatin architecture.
Recently, N6-adenine methylation has been found in the In addition, most functional studies on CG antigens have been
mammalian genome and is reported to be a crucial regulator of performed on CT-X antigens only, which may be because of highly
gene expression in embryonic stem cells and cancer cells. N6- similar paralogous sequences of pericentromeric genes, which pose
methyladenine is responsible for epigenetic silencing of young difficulty in expression analysis of any specific transcripts from
LINE-1 elements along with enhancers and genes in the near vi- many duplicated regions on different chromosomes. A detailed list
cinity and controls embryonic stem cell differentiation (Wu et al., of CT antigens is provided in the CT database. Most notably, many
2016). While the X chromosome and PCH are rich in these LINE-1 curated genes are located at the pericentromere. CT antigens have
transposons, the role of N6-adenine methylation in the regulation roles in mitosis, cell division, cell motility, EMT, cell structure
of X-chromosomal or pericentromeric genes remains to be maintenance, and chemotherapy resistance (Cappell et al., 2012;
explored. Gjerstorff et al., 2016; Soltanian and Dehghani, 2018). While most of
the current CT/CG antigen-targeted cancer vaccines have utilized
CT-X antigens, several non-CT-X antigens present on the pericen-
Histone modification at the pericentromere tromere have shown antigenic potential been proposed as prom-
ising immunotherapeutic targets. Many reports have shown that
There are distinct patterns of histone modifications that differ- heterochromatin genes, including CT antigens, are epigenetically
entiate euchromatin from heterochromatin. While euchromatin is regulated (Grunwald et al., 2006; James et al., 2013; Sharma et al.,
enriched with H3 and H4 acetylation and active histone methyl- 2019). DNA hypomethylating drugs have been shown to induce
ation marks, such as H3K36me3 (histone H3 lysine 36 trimethyla- pericentromeric gene expression (Sharma et al., 2019) along with
tion), H3K79me2, and H3K4me3 (Hyun et al., 2017); PCH is other CT antigens (Natsume et al., 2008).
enriched with repressive histone modifications, such as H3K9me2, Some CT antigens are important in regulating tumor cell divi-
H3K9me3, H3K27me1, and H4K20me3 (Khalil and Driscoll, 2010). sion, and when targeted, they show synthetic lethality with
4
Table 1
List of epigenetic marks present at pericentromere and play a crucial role in pericentromeric heterochromatin formation and gene regulation.
Epigenetic modification Position of Enzymes involved Functions References

modification/Marks
DNA methylation (Peri)centromeric DNA DNMT1, DNMT3A, Transcriptional repression at pericentromere Bird (2002); Gopalakrishnan
at cytosines in CpG and DNMT3B Loss of DNMTs leads to overproduction of et al. (2009)
dinucleotides pericentromeric transcripts
Histone methylation H3K9me Prdm3 and Prdm16, Constitutive heterochromatin formation at Loyola et al. (2009); Pinheiro
KMT, SETDB1 pericentromere et al. (2012)
H3K9me2/3 SUV39H1/2 (also Generation of the binding site for HP1 protein Lachner et al. (2001)
called KMT1A/B) leading to chromatin compaction and silencing
H3K27me1/2 G9A complex Gene repression Tachibana et al. (2001); Wu
et al. (2011)
H3K27me2/3 Polycomb Regulates transcriptional repression Wiles and Selker (2017)
repressive complex
2(PRC2), H3K27
methyltransferase
EZH2 (also called
KMT6A)
H4K20me2/3 SUV420H enzymes Hallmark of constitutive heterochromatin at Sakaguchi et al. (2008)
(also called KMT5B) pericentromere
H4K20me SIRT1 Heterochromatin formation and chromatin Jørgensen et al. (2013)
compaction at pericentromere
H3K4me1/2 MLL1/2 core Transcriptional activation Patel et al. (2009)
complexes with
WRAD
H3K36me2/3 SETD2 Transcriptional activation Edmunds et al. (2008)
Histone acetylation H4K5ac, H4K12ac RbAp46/48eHat1 Abundant in centromere; results in Shang et al. (2016)
complex centromere-specific histone H3 variant CENP-A
deposition into centromeres
H3K18ac GCN5 Pericentromeric gene activation, genomic Tasselli et al. (2016)
instability
Histone deacetylation H3K14 histone deacetylase Chromatin compaction Smurova and De Wulf (2018)
Clr3 (HDAC1)
H4K16 SIRT1, SIRT6 H4K16 deacetylation is a hallmark of cancer Fraga et al. (2005); Vaquero
et al. (2007b)
H3K9 SIRT1 H3K9 deacetylation by SIRT1 facilitates Vaquero et al. (2007a)
SUV39H1 mediated addition of H3K9me2/3
repressive mark at pericentromere
H4K5; H4K12 HDAC3 Restores chromatin structure allowing proper Eot-Houllier et al. (2008);
inter-nucleosomal interactions Bhaskara et al. (2010)
Histone demethylation Demethylation of Heterochromatin- Depletion of KDM2A leads to loss of HP1 and Frescas et al. (2008)
H3K36me2 associating lysine elevation of alpha-satellite and MajSat
demethylase 2A transcription
(KDM2A) inhuman and mouse cells
Demethylation of histone Reduction of H3K9me3 marks at CEN causing Slee et al. (2012)
H3K9me3 demethylase chromosomal instability
JMJD2B
minimal chemotherapy dosage (Cappell et al., 2012). Several re- including breast, prostate, and hematopoietic malignancies
ports have suggested comparing the expression of CT antigens in (Barutcu et al., 2015; Wu et al., 2017; Yang et al., 2019). Thus,
normal stem cells prior to targeting. While several CT-X antigens investigating the nuclear architecture and spatial genome organi-
are expressed as cancer stem cell markers (Ghafouri-Fard, 2012), zation are essential for understanding cancer-associated aberrant
the expression of pericentromeric genes has been less explored, gene expression mechanisms. This section will discuss the basics of
and very few genes have been analyzed, for example, BAGE, TPTE, nuclear compartmentalization, the spatial organization of PCH, and
and POTE. BAGE2 expression is correlated with high-grade multiple how the alteration in PCH organization is associated with cancer-
myeloma (Ghafouri-Fard, 2012). Pericentromeric POTE gene family associated aberrant expression of pericentromeric transcripts.
members have been implicated as cancer biomarkers (Barger et al.,
2018; Sharma et al., 2019; Singh et al., 2019). Table S1 shows a list of
Nuclear compartments
different pericentromere-localized CTAs that are aberrantly
expressed in many cancers.
The genome inside the 3D nucleus is not linearly positioned,
rather it exhibits distinct hierarchical patterns of organization.
Overview of the nuclear architecture and pericentromeric Most of the information we know today regarding genome orga-
heterochromatin organization nization come from microscopy studies such as FISH and C-tech-
nologies, such as chromosome conformation capture (3C) and its
In higher eukaryotes, genome organization inside the three- higher-order derivatives (Hi-C). Genome organization inside the
dimensional nucleus is crucial for gene expression and its regula- nucleus occurs at different levels, designated as structural and
tion. Changes in the genomic architecture are detrimental and are spatial organization. While structural organization shows intra-
related to aberrant expression of many genes that give rise to a chromosomal interactions and the formation of distinct topologi-
spectrum of disease conditions, including cancer. The alteration of cally associated domains (TADs), the spatial organization addresses
3D genome architecture is widely studied in many kinds of cancers the highly folded genome’s physical position inside the three-
5
dimensional nuclei. The primary genome organization is simply the genomic regions that make molecular contact with the NL (Guelen
gene sequence, which then undergoes further compaction into the et al., 2008). These genomic regions were mapped using Dam-ID
nucleosome structure that is contemplated as the basic unit of the technology (Pickersgill et al., 2006). Dam-ID is based on tethering
higher-order chromatin conformation. Nucleosomes are again an NL protein to the DNA adenine methyltransferases (Dam) of
compacted several-fold and subsequently form chromatin loops, Escherichia coli, which methylates the adjacent adenine residue in
TADs, chromosome compartments, and chromosome territories the GATC sequence of the genome that makes molecular contacts
(Krumm and Duan, 2019). (Fig. 1A). with NL proteins (Vogel et al., 2007). Subsequent detection of this
m6A methylation by microscopy and genome-wide sequencing
Lamina-associated domains leads to the generation of the Dam-ID map that reveals genome-
wide contact maps to the NL. LADs are exciting primarily because
The organization of human chromosomes in the interphase their NL anchorage helps regulate the interphase chromosome to-
nuclei was obscure until microscopic studies demonstrated that pology and genome architecture. The interaction of the NL with the
regions of chromosomes are situated in the immediate vicinity to genome results in low expression of the genes present in the LAD
the NL (Fawcett, 1966). This finding has prompted the possibility region. LADs have been mapped in Drosophila melanogaster, Cae-
that certain genomic components might be appended to the NL, norhabditis elegans, and human lung fibroblast cell lines (Pickersgill
regulating the spatial organization of chromosomes inside the et al., 2006; Guelen et al., 2008; Ikegami et al., 2010; Peric-Hupkes
nucleus. These genomic regions are termed LADs and defined as the et al., 2010). LADs mostly range from 10 kb to 10 Mb in size (0.5 Mb
Fig. 1. Overview of 3D genome organization and genome-nuclear lamina interaction. (A) Schematic representation of the genome organization inside a 3D nucleus. Genome
organization inside the 3D nucleus is nonrandom during interphase and exhibits distinct hierarchical patterns. Chromosomes maintain distinct territories. Gene-rich euchromatin
regions are positioned at the nucleus’ interior and form several TADs. Simultaneously, the gene-poor heterochromatin is placed at the nuclear periphery in close association with the
nuclear lamina and named as LADs, conventionally known as peripheral heterochromatin. The second heterochromatin category is also present and interacts with nucleolus
(nucleolus-associated domains/perinucleolar heterochromatin). (B) Organization of nuclear LADs. Large heterochromatin blocks making molecular contact with the nuclear lamina
(approximately 40% within the genome). LADs display several epigenetic marksdH3K9me2/3 at the LAD body and H3K27me3 at the borders. Presently there are three models
regarding LADs-NL interaction: 1. Being inactive heterochromatin LADs are passively pushed toward nuclear periphery; 2. Specific DNA sequence tethers LAD to interact with NL or
NL-associated proteins; 3. Epigenetic marks present on LADs could be read by epigenetic readers present at the nuclear lamina. Detachment from nuclear lamina transcriptionally
activates genes located at LAD regions. TAD, topologically associated domain; LAD, lamina-associated domain; NL, nuclear lamina.
6
median) and are present across all the chromosomes. Typical distinct nuclear microenvironment termed as ‘nuclear foci’ which
mouse and human cells have 1,000e1,500 LAD regions covering facilitates the recruitment of several DNA damage molecules into
over one-third of the genome, making them one of the important that site (Kuo and Yang, 2008). Thus, nuclear microenvironments
features of the epigenome in these organisms (van Steensel and and not isolated biochemical changes inside the nucleus are sup-
Belmont, 2017). The genes present in the LAD region are dilatory posed to be responsible for multidimensional cancer-associated
replicating and mostly transcriptionally silenced. Several histone changes (Nozawa et al., 2020).
modification marks are enriched in LAD regions, such as H3K9me2 The question arises regarding the mechanism of formation of
and H3K9me3 histone marks are present in the LAD body, and the these nuclear subcompartments because constant diffusion across
LAD boundaries are marked by H3K27me3 (Guelen et al., 2008) the nuclear interior balances the gradient of soluble components
(Fig. 1B). Several studies have reported that LADs can be constitu- inside the nucleus. Different biophysical phenomena elucidate self-
tive or facultative depending on their consistency of NL association organizing nuclear subcompartment formation. One such mecha-
in different cell types. Some LADs interact with the NL in all cell nism explains nuclear bodies formation through cooperative
types; these LADs are termed constitutive LADs (cLADs) while some binding of proteins involved in binding with the chromatin struc-
LADs interact with the NL only in some specific types of cells and ture at different chromatin binding sites and among each other
not in the other cell types; these are termed facultative LADs (Wachsmuth et al., 2008). Sequence-specific interaction and feed-
(fLADs) (Peric-Hupkes et al., 2010; Meuleman et al., 2013). More- back loop mechanisms are two such mechanisms that rationalize
over, cLADs are predominantly gene-poor and rich in LINEdbut this concept (Fig. 2A). In the case of mammals, PCH nucleation
poor in short interspersed nuclear elements, whereas fLADs are the depends on SUV39 enzymes that are involved in recognizing sat-
gene-dense region within the LADs and make up more than half of ellite repeat DNA sequences within the pericentromere (Müller-Ott
all LADs. The genomic positions and sizes of fLADs are mostly et al., 2014). In addition, the spreading of heterochromatin has been
variable among mice and humans compared with the cLAD posi- seen by the recruitment of HDAC by heterochromatin protein 1
tion and size, which shows strong conservation between these two (HP1) (Yamada et al., 2005; Fischer et al., 2009). Therefore, the
organisms (Meuleman et al., 2013). interplay between the writer, reader, and eraser of epigenetic
marks tends to form a positive feedback loop that subsequently
Liquid-liquid phase separation and PCH structuring reinforces the heterochromatin state and its progression (Allshire
and Madhani, 2018).
Over a decade ago, the concept of nuclear microenvironments Besides, two other mechanisms have also been proposed that
was proposed by Zaidi et al. (2007), which was demonstrated as a specifically focus on phase separation within the nuclear compo-
platform for nuclear machinery’s spatial organization. Under stress, nents to form heterochromatin subcompartments. These are
the nuclear microenvironment organization is significantly altered. termed polymer-polymer phase separation (PPPS) and liquid-liquid
For example, in response to DNA damage, phosphorylation of his- phase separation (LLPS). LLPS is defined as formation of a liquid
tone proteins take place inside the chromatin at the damage site droplet when de-mixing of a liquid phase with multiple distinct
which also extends to the adjacent chromatin regions and forms a phases take place. Weak and multivalent interactions among
Fig. 2. Mechanisms of PCH structuring through liquid-liquid phase separation (LLPS). (A) Different types of phase separation that drive higher-order heterochromatin organization.
Formation of heterochromatin subcompartments can be achieved by binding a chromatin-binding protein into its binding site within the nucleosome by sequence-specific
interaction or feedback loop mechanism without any phase separation. Some proteins serve as a bridging factor for the chromatin organization and cross-link chromatin re-
gions at the spatial proximity and form ordered globule structure, thereby leading to polymer-polymer phase separation (PPPS). Chromatin binding proteins that exhibit multivalent
interaction lead to a stable liquid-like droplet and chromatin, leading to liquid-liquid phase separation (LLPS). Liquid droplets formed through LLPS are stable even without the
chromatin scaffold. (B) PCH structuring mediated by HP1 protein. HP1 binds to H3K9me3 regions enriched in the PCH region and mediates higher order PCH organization via liquid-
liquid phase separation. (C) PCH organization mediated by SAFB protein. SAFB binds to MajSAT RNA expressed from the pericentromeric region and promotes higher-order
structuring of PCH through LLPS. Depletion of SAFB in cancer leads to decompaction of pericentromeric heterochromatin. PCH, pericentromeric heterochromatin; HP1, hetero-
chromatin protein 1; SAFB, scaffold attachment factor B; H3K9me3, histone 3 lysine 9 trimethylation.
7
chromatin-binding proteins are the key factors that lead to the important for transcriptional regulation. Currently, we have a clear
development of a higher-order heterochromatin scaffold via LLPS. understanding of the epigenetic mechanisms that play a crucial role
Inside the cell, there are several proteins and RNA molecules that in PCH regulation both at normal somatic cells and in cancerous
showcase multivalent interactions among themselves. These conditions. However, the 3D organization of PCH in somatic cells
include RNA-binding proteins harboring intrinsically disordered and its defects in cancerous conditions still requires extensive
regions (also known as low complexity regions, as these harbor study. Earlier microscopy-based studies proved to be an important
limited amino acids) that co-assembly to form phase-separated technique for studying PCH organization and its aberration in dis-
liquid droplets (Lin et al., 2015; Xiang et al., 2015). Multivalent in- ease conditions. Currently, along with microscopic techniques,
teractions between different molecules gives rise to supramolecu- high-throughput sequencing and Hi-C based techniques are also
lar cluster formation. For LLPS-driven condensate formation, these most useful for an in-depth analysis of the 3D architecture of the
multivalent interactions within interacting molecules should be PCH. We present a list of techniques potentially useful for 3D
strong enough compared with their interaction with solvent and genome analysis in Table 2. However, the initial knowledge
weak enough so that irreversible aggregation can be induced. This regarding 3D genome architecture was predominantly based on the
process leads to the formation of a high-density liquid phase that euchromatin region and typically ignored PCH regions because of
can comparatively coexist with a less dense liquid phase (Erdel and the abundant presence of repetitive sequences in it. The presence of
Rippe, 2018), leading potentially to the enrichment of certain bio- repeat sequences into sequencing reads has always made their
molecules into one phase, which ultimately results in the activation analysis more challenging because of their ambiguity during
or inhibition of certain biochemical reactions (Fig. 2A). alignment and assembly. Traditionally, Hi-C results analysis for
Recent findings revealed that the formation of PCH also involves constructing a 3D genome interaction map also ignored PCH region
liquid-liquid phase separation. Heterochromatin protein 1a has for the same reason. More recently, Lee et al. (2020) have devised a
been reported to be involved in forming CH enriched for repetitive novel computational analysis method that enabled the PCH region’s
sequences via LLPS in mammals and Drosophila (Larson et al., 2017; detection from genome-wide Hi-C data. In this analysis method,
Strom et al., 2017). Like many other proteins involved in LLPs, the the authors included three types of PCH-derived reads (sequences)
HP1 protein possesses three distinct domains: an intrinsically such as 1) single copy unique reads, 2) known heterochromatin
disordered region, a dimerization domain, and a substrate-binding reads (repeat reads), and 3) multimapped reads (nonunique se-
domain that specifically binds H3K9me2/3 repressive marks. It has quences within PCH) and constructed contact maps for
also been shown that HP1 can readily form liquid droplets via phase euchromatin-pericentromeric heterochromatin (EU-PCH) and
separation in an in vitro model system. As described previously, PCH-PCH itself. Using the same method, the authors showed that
pericentromeric regions are rich in such histone repressive marks the PCH in Drosophila melanogaster embryos is hierarchically
which conversely explains why HP1 is an important candidate for organized into distinct territories and exhibits spatial contact with
PCH structuring via LLPS (Fig. 2B). H3K9me2/3 rich domains in euchromatin in a manner that
The higher-order structuring of centromeric and PCH rich in resembled LLPS (Lee et al., 2020). The authors also reported that
repetitive sequences has also been described by a mechanism PCH regions from different chromosomes are involved in forming a
where self-interaction among repetitive sequences drives the 3D PCH domain that is consistent with the previously delineated
generation of repeat assemblies, which ultimately lead to the for- chromocenter structure (Lee et al., 2020). We give a list of other
mation of chromatin organization via phase separation (Tang, computational tools that are important for repetitive sequence
2011a, 2011b, 2012). While it is obvious that DNA with repeat- analysis in Table 3.
rich sequences exhibits extensive self-interaction (Inoue et al., It has been shown previously that PCH regions from different
2007; Tang, 2011b; Nishikawa and Ohyama, 2013; Gladyshev and chromosomes form chromocenters inside the 3D nuclei, thereby
Kleckner, 2014), the formation of such phase-separated chromatin maintaining stable repression of genes (Zhang and Spradling, 1995;
assembly is desirable. Mayer et al., 2005). The formation of chromocenter has been re-
More recently, Huo et al. (2020) demonstrated that the forma- ported in fission yeast (Funabiki et al., 1993), plants (Fransz et al.,
tion of a higher-order organization of PCH depends on the nuclear 2002), and humans (Bartholdi, 1991; Alcobia et al., 2000). Inside
matrix protein scaffold attachment factor B (SAFB) via phase sep- the mammalian cells, it has been observed that centromeric clus-
aration. SAFB is a RNA-binding protein that contains an RGG motif ters often tend to form toward the nuclear periphery or around the
and SAP domain (Norman et al., 2016). SAFB is involved in an nucleolus (Haaf and Schmid, 1991). The repressive H3K9me3 mark
interaction with MajSAT RNA (major satellite RNA expressed from at PCH serves as a docking site for the HP1 present on the nuclear
repeat-rich centromeric and pericentromeric regions) through its periphery (Jacobs et al., 2001). The role of HP1 in PCH structuring
RGG motif and promotes PCH organization through phase separa- through LLPS is already described in the previous section. HP1
tion (Fig. 2C). A reduction in SAFB levels is associated with a global serves as a bridge between NL and heterochromatin, maintaining a
change in genome organization, including reduced compartmen- peripheral heterochromatin (PH) position inside the nucleus.
talization of the genome and loosening of chromatin at the peri- Dam-ID and microscopy-based studies have previously
centromeric region (Huo et al., 2020). SAFB mutation and demonstrated that the centromeric region is preferentially located
downregulation are well documented in many kinds of cancers, at the nuclear periphery, although there are variations from cell to
such as colon cancer (Jiao et al., 2017), prostate cancer cell (Solovei et al., 2004; Guelen et al., 2008). Recently, it has been
(Mukhopadhyay et al., 2014), and breast cancer (Oesterreich et al., shown that the pericentromere-associated domains (PADs) from
2001), which strongly suggests a mechanistic link between mouse embryonic stem cells harbor identical chromatin states with
cancer-associated remodeling of PCH and pericentromeric satellite non-PADs. However, chromocenters move toward the CH present
transcription. at the nuclear periphery at the time of cellular differentiation
(Wijchers et al., 2015). This suggests that there is a possibility that
Spatial organization of pericentromeric heterochromatin and PCH is positioned at the NL together with other LADs present in that
links with gene regulation in cancer region. Furthermore, it has been shown by using FISH and Dam-ID
that peripheral localization of late replicating chromatin depends
It has long been thought that the nuclear architecture and the on chromosome size and gene density. The tendency of late repli-
spatial organization of the genome inside the 3D nucleus are cating DNA present on small chromosomes to localize at the
8
Table 2
List of different techniques used for 3D genome analysis.
Techniques Functions limitations References
Hi-C Can detect interactions even over large genomic The relationship between spatial distance and the Barutcu et al. (2016);
distances number of Hi-C contacts is not clear Liu and Wang (2018)
Single-cell Hi-C Can investigate genome-wide chromatin interaction in Sparse and noisy data Kim et al. (2020)
individual cells
DNase Hi-C Global and local three-dimensional genome Bait-targeted region can get digested by DNase I Ma et al. (2018)
architecture can be mapped at high resolution treatment
In situ Hi-C Diminishes the number of false contacts that can arise Not appropriate for probing local intra-TAD interactions Ando-Kuri et al. (2018)
from ligation proximity (<40 kb)
Capture-C Long-range DNA interactions can be detected Large amounts of starting material are required due to Hughes et al. (2014)
multiple steps
3C Perform high-throughput Insensitive for high-throughput identification of novel Han et al. (2018)
looping interaction
ChIP-loop Can reduce background noises in 3C experiments Throughput is limited Dekker and Misteli
(2015)
4C Highly reproducible data Local interactions (<50 kb) from the region of interest Barutcu et al. (2016)
are missed generally
5C A matrix of interaction frequencies for many pairs of Random chromosomal collisions can also give false Dostie et al. (2006)
sites are provided results
ChIA-PET Reduce complexity and adds specificity in genome- The quality, purity, and specificity of the antibodies Fullwood et al. (2009)
wide interactions. used are limited.
periphery is much lower; rather, it tends to move toward PCH and heterochromatin subcompartments (PH, PCH, and PNH), which
perinucleolar heterochromatin (PNH) for association (Ragoczy suggested a functional redundancy among these subcompartments
et al., 2014). The multicolor-FISH experiment suggested that there (Ragoczy et al., 2014). Several studies also reported a partial overlap
could be an association of late replicating genes, especially those between PNH (also termed as nucleolus associated domains or
located on smaller chromosomes, with any of the repressive NADs) and nuclear LADs. Using FISH microscopic analysis has also
Table 3
List of different computational tools useful for the analysis of repetitive sequences.
Type Technique Function Website References
Library based REPEATMASKER Detect assemblies and genes by masking http://www.repeatmasker.org RepeatMasker Home Page
repeats in sequences (1997)
CENSOR Screens query sequences and masks http://www.girinst.org/censor/ Jurka et al. (1996)
homologous portions against a chosen download.php
reference sequence of repeats
PLOTREP Resolve problem during similarity searches http://repeats.abc.hu/cgi-bin/ th et al. (2006)
To
against a library plotrep.pl
LTR_STRUC Identify LTR retrotransposons by scanning http://www.mcdonaldlab. McCarthy and McDonald (2003)
nucleotide sequence files. biology.gatech.edu/
Signature-based FINDMITE Detect MITEs http://jaketu.biochem.vt.edu/ Tu (2001)
dl_software.htm
MAK Automated MITE analysis Not available Yang and Hall (2003)
PILER Enhances reliability by identifying http://www.drive5.com/piler/ Edgar and Myers (2005)
alignments that form specific patterns of a
given repeat type.
RECON Identify repeat sequence families from http://selab.janelia.org/recon. Price et al. (2005)
genomic sequences html
Ab initio FORRepeats Detection of repeats on entire http://al.jalix.org/FORRepeats/ Lefebvre et al. (2003)
chromosomes and between genomes
RepeatScout Recognize repetitive substrings in DNA http://repeatscout.bioprojects. Price et al. (2005)
org/
RepeatGluer Identification of TEs purely from sequence http://nbcr.sdsc.edu/euler/ Kurtz et al. (2008)
content, intro_tmp.htm
MUMmer Quick alignment of entire genomes http://mummer.sourceforge. Delcher et al. (1999)
net/
RAP Identify repeated sequences de novo in http://genomics.cribi.unipd.it/ Campagna et al. (2005)
whole genomes index.php/Rap_Repeat_Filter
REPuter Analyze repetitive DNA on a genomic scale http://www.genomes.de/ Kurtz and Schleiermacher
(1999)
RepeatFinder Search repetitive sequences complete and http://cbcb.umd.edu/software/ Kurtz et al. (2008)
draft genomes RepeatFinder/
Spectral Repeat Finder Find repeats by analysis of the http://www.imtech.res.in/ Sharma et al. (2004)
power spectrum of a given DNA sequence raghava/srf/
REAS Screening unassembled reads of a whole- ftp://ftp.genomics.org.cn/pub/ Li et al. (2005)
genome shotgun to recover ancestral ReAS/software/
sequences for transposable elements (TEs)
Vmatch solve large scale sequence matching tasks http://www.vmatch.de/ Healy et al. (2003)
Classification programs OMWSA Detect DNA repeats in a 2D plane of location http://www.hy8.com/Btec/ Du et al. (2007)
sw01/omwsa01.zip
9
Fig. 3. The interplay between PCH organization and epigenomic alterations during cancer. (A) Schematic representation of pericentromeric region within chromosome. (B) Cancer-
associated epigenome remodeling at pericentromere and its orchestration with genome architecture inside the nucleus. In normal somatic cells, the PCH is usually located at the
nuclear periphery and forms constitutive heterochromatin. Epigenomic alterations such as DNA hypermethylation, the addition of repressive chromatin marks (H3K9me2/3,
H3K27me3), deacetylation, and demethylation at H3K36 position leads to CH formation, thereby maintaining the genomic stability. In cancer cells, big epigenomic changes (DNA
hypomethylation, histone acetylation at H3K18, and H3K36me2/3) lead to activation of the pericentromeric locus, and aberrant pericentromeric transcripts cause genomic
instability and ultimately progression of cancer. Whether or not these cancer cells associated with epigenetic changes are attributed to change of 3D positioning of the PCH and
detachment from NL is still elusive. But a strong mechanistic link between PCH reorganization and epigenome alteration could exit that lead to pericentromeric gene activation in
cancer. CH, constitutive heterochromatin; PCH, pericentromeric heterochromatin.
been shown that some nucleolus associated domains are found to replicating regions within the chromatin, rather than considering
be located near the nuclear lamina. Single-cell Dam-ID and ‘mo- these as individual subcompartments. Thus, we can imagine a
lecular contact memory’ approach reported reshuffling of LADs whole distribution of large heterochromatin blocks within all three
after mitosis, which results in the positioning of LADs in contact domains. Despite these heterochromatin domains have over-
with nucleolus from parent to daughter cells (Kind et al., 2013). A lapping sequences, they are unique from a functional point of view.
similar result was also reported using fluorescence photoactivation Depending on the cell type and cellular conditions, some domains
and high-resolution DNA sequencing, which shows that certain loci (cLADs) are preferentially tethered to the NL. Others are distributed
within the chromatin can associate with either NL or nucleolus among any three compartments within the nucleus except those
(Van Koningsbruggen et al., 2010). Moreover, PCH, PNH, and PH located at the small chromosomes and show preferential tethering
could be considered as a functional compartment for late toward nucleolus, keeping the epigenomic landscape similar.
10
Now, the questions are how this spatiotemporal organization of genes are very actively transcribed (Guelen et al., 2008). How these
the PCH is controlling gene expression and whether cancer- genes escape repression is still elusive.
associated pericentromeric gene activation has an overall impact It is currently evident that cancer harbors large epigenomic
on the 3D genome architecture and vice versa. While many studies changes, such as hypomethylation of oncogenes and hyper-
have showed that altered localization of genomic regions accom- methylation of tumor suppressors (Esteller, 2002; Ehrlich, 2009).
panied by epigenomic changes, which leads to changes in gene Even cancer-associated pericentromeric gene expression has
expression during cellular processes (Peric-Hupkes et al., 2010) and shown hypomethylation at those gene promoters. However, the
disease conditions like cancer (Reddy and Feinberg, 2013), the exact interplay between the three-dimensional organization of PCH and
cause-and-effect relationship between chromatin localization and the cancer methylome requires substantial attention from the sci-
gene expression remain largely elusive. In cells of the ICF patient, a entific community. Even the time frame of reprogramming of PCH
significant change in the intranuclear position of PCH is observed, and its 3D positioning is crucial to address. Besides, the role of
suggesting a strong mechanistic link between the nuclear archi- transcription factors in this spatiotemporal arrangement and
tecture organization and the altered gene expression (Tessier et al., driving pericentromeric gene transcription is enigmatic. Taken
2012). Some studies have linked LAD organization with global together, the current understanding strongly suggests that there is
cancer methylome changes (Hansen et al., 2011; Berman et al., a very complex and coordinated interplay between all these factors
2012; Hon et al., 2012). These studies have reported a large over- that are somehow altered in cancer, giving rise to aberrant peri-
lap of LADs and LOCKs (large organized chromatin lysine modifi- centromeric gene expression. Present-day high-throughput geno-
cations; a genomic region with a high abundance of H3K9me2) mics, coupled with high-resolution microscopic analysis, could
with partially methylated domains in human colon cancer. Inter- help understand this area.
estingly, short regions of hypermethylated promoter CpG islands
have been found on the borders of these large hypomethylated Acknowledgments
domains and involved in transcriptional repression of tumour-
suppressor genes (Berman et al., 2012). These results raise the The authors thank the All India Institute of Medical Sciences,
question, whether gene repression at the NL can be attributed to New Delhi, India, for providing all necessary support. They thank
the cancer-associated hypermethylation of LAD borders, as LAD the Department of Science and Technology (DST-SERB), India, for
borders exhibit a higher abundance of CpG sites. Similarly, cancer- funding (DST grant number: ECR/2016/001740). SK thanks Univer-
specific gene activation could also be possible by the physical sity Grants Commission, India, for fellowship support. The authors
separation from NL by this mechanism. Whatever it may be, these report no conflict of interest.
studies provide strong mechanistic insights into the involvement of
LADs and the change in nuclear architecture with the development Supplementary data
of cancer. Although, at present there is no such study that directly
links global change in nuclear architecture with the pericentro- Supplementary data to this article can be found online at
meric gene activation in cancer, the current understanding in this https://doi.org/10.1016/j.jgg.2021.02.004.
field lead us to hypothesize that there may be a coordinated
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Journal of Genetics and Genomics

Interplay between genome organization and epigenomic alterations of

Introduction supporting strong epigenetic regulation to maintain cellular iden-

Epigenetic modiﬁcation Position of Enzymes involved Functions References

Techniques Functions limitations References

Type Technique Function Website References

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