Non-coding RNA Research 5 (2020) 178–184

Contents lists available at ScienceDirect

Non-coding RNA Research

journal homepage: http://www.keaipublishing.com/ncrna

The physiological function of long-noncoding RNAs T

He Chen , Ge Shan
∗ ∗∗

CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and
Technology of China, Hefei, Anhui Province, 230027, China

ARTICLE INFO ABSTRACT

Keywords: The physiological processes of cells and organisms are regulated by various biological macromolecules, in-
Long noncoding RNA cluding long-noncoding RNAs (lncRNAs), which cannot be translated into protein and are different from small-
LincRNA noncoding RNAs on their length. In animals, lncRNAs are involved in development, metabolism, reproduction,
CircRNA aging and other life events by cis or trans effects. For many functional lncRNAs, there is growing evidence that
CRISPR
they play different roles on cellular level and organismal level. On the other hand, many annotated lncRNAs are
Phenotype
Physiological function
not essential and could be transcription noises. In this minireview, we investigate the physiological function of
lncRNAs in cells and focus on their functions and functional mechanisms on the organismal level. The studies on
lncRNAs using different classic animal models such as worms and flies are summarized and discussed in this
article.

1. Introduction noncoding RNA, Hotair regulates epidermal cell differentiation and

interacts with epigenetic factors such as PRC2 to participate in tumor
Recent studies illustrate varieties of noncoding RNAs which lack metastasis [16,17]. Although Hotair plays a key role in cultural cells,
ORFs and cannot translate. Noncoding RNAs can be classified according one study suggested that Hotair were dispensable for whole animals
to their location, function, size or secondary structure [1,2]. The non- [18]. Hotair knockout mice did not exhibit the expecting phenotypes
coding RNAs with the length of hundreds (200) nt or more are long suggesting they are not necessary for mouse development and em-
(large) noncoding RNAs (LncRNAs) [3,4]. LncRNAs can be linear or bryonic survival [18]. The same also occurred in the study of Malat1
circular, distributed in the nucleus, cytoplasm and mitochondria [5–8] [19–22].With the advances of technology, especially CPRISPR gene
(Fig. 1). According to the distribution of lncRNAs in the genome, re- editing and Next-generation sequencing, a growing body of lncRNA
lative positions with nearby coding genes and transcription directions, researches are conducted at the whole-organism scale. In this review,
they can be divided into four groups: long intervening/intergenic we summarize the physiological functions and mechanisms of lncRNAs
noncoding RNAs(lincRNAs), intronic lncRNAs, sense lncRNAs and an- in cells and animal models.
tisense lncRNAs [3]. According to their functions, lncRNAs can be
roughly divided into: functional lncRNAs, whose transcripts can reg- 2. Cellular physiological functions of LncRNAs
ulate genes expression in cis or in trans; lncRNAs play their roles during
transcription, but their transcripts have no functions; no functions 2.1. lincRNAs
lncRNAs which might be transcription noises [9–11].
In cells, lncRNAs which located in the nucleus or cytoplasm interact Long intervening/intergenic noncoding RNAs(lincRNAs) are
with DNAs, proteins or other RNAs. They involve in the cell's pro- lncRNAs located between coding genes and have no overlap with any
liferation, differentiation and apoptosis [12]. In animals, lncRNAs play annotated protein-coding sequences. LincRNAs exercise physiological
their functional roles in development, reproduction, aging and disease functions in cells such as carcinogenesis, infection and inflammation.
[12–14]. Interestingly, in some cases, the key roles of lncRNAs in cells For example, NEAT (Nuclear Enriched Abundant Transcript) RNAs in-
do not match their importance at the whole-organism scale, for ex- cluding Neat1 and Malat1(also named as Neat2), are classic examples of
ample, knockout almost all lincRNAs one by one in nematodes did not lincRNAs in mammalian cells and are involved in carcinogenesis
exhibit critical phenotypes [15]. In mammals, a widely studied long [23–27]. They are conserved across various mammals and locate in the

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: [email protected] (H. Chen), [email protected] (G. Shan).

https://doi.org/10.1016/j.ncrna.2020.09.003
Received 11 September 2020; Accepted 15 September 2020
Available online 17 September 2020
2468-0540/ © 2020 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

Fig. 1. Types of long-noncoding RNA(linear and circular). (A) 4 groups of lncRNA according to the distribution of lncRNAs in the genome, relative positions with
nearby coding genes and transcription directions. (B) 4 groups of circRNA in cytoplasm, nucleus and mitochondria.

nuclear and participate in many biological processes such as para- 2.2. Circular RNAs
speckle formation, cell cycle regulation, alternative splicing and cancer
cells migration [28,29]. Another extensively studied lincRNA Hotair Not only linear but also circular long noncoding RNAs modulate
which located in HOXC gene cluster, is a highly expressed gene in cellular physiological processes [38–40]. Circular RNAs are generated
metastatic breast cancers [30,31]. Hotair interacts with Polycomb- by back-splicing from precursor mRNAs and displayed special expres-
group proteins and reprogram chromatin state in trans [32,33]. sion pattern in tissues and developmental stages [41–44]. In general,
LincRNA-p21 activated by tumor suppressor P53, is another important circular RNAs are roughly divided into four categories: Exonic circRNA,
transcriptional repressor that binds to the hnRNP family protein circular intronic RNAs (ciRNAs), exon–intron circRNAs (EiciRNAs) and
hnRNP-K after DNA damage and participates in maintaining of the P53 mitochondria-encoded circRNA(mecciRNAs) [7,8,45,46]. Circular
induced genome stability [34]. Not only lincRNAs could be taken as RNAs can function as microRNA sponges and regulate genes expression
regulators and biomarkers in tumor cells, but also functional molecules in trans [47,48]. For example, CDR1as(ciRS-7) can bind miR-7 and miR-
for cellular physiology. For instance, lincRNAs with elevated expression 671 to regulate the expression of their target genes and functions in
patterns in iPS and ES cells suggest their functions in establishment and cellular proliferation and apoptosis [49–51]. CDR1as knockout mice
maintenance of pluripotency [35,36]. In pluripotent stem cells, displayed abnormal brain function due to the defect of synaptic neu-
lincRNA-RoR modulates reprogramming as the direct targets of key rotransmission [52]. CDR1as is also a regulator of insulin secretion and
transcription factors [35]. In other studies, lincRNAs played their roles oncogene [53,54]. On the other hand, Circular RNAs can act as protein
in immunomodulation such as lincRNA-EPS. It acts as an important sponge, decoy or scaffold [55,56]. For example, Cia-cGAS acts as nu-
regulator of immune response genes in immune cells in trans [37]. clear cGAS sponge to block its enzymatic activity in hematopoietic stem

179
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

cells to protect their homeostasis [55]. In another research, circ-Foxo3 manner, and many of them are dauer stage-specific or sperm-specific
constructs circ-Foxo3-p21-CDK2 complex to block cell cycle progression molecules [15,70]. To investigate their spatiotemporal expression,
by suppressing CDK2 [56]. Circular RNAs are also able to function in transgenic reporter strains and RNA-seq were generated showing that
cis. Take EiciRNAs as an example, which are circularized with introns the expression patterns of lincRNAs are more specific and hetero-
“retained” between their exons [7]. EiciRNAs such as circEIF3J and geneous than transcription factors [71]. LincRNAs of C. elegans can be
circPAIP2 can hold U1 snRNP by specific RNA-RNA interaction, then detected in different developmental stages and tissues including intes-
the complexes further interact with the Pol II at the promoters of par- tine cells, hypodermal cells, muscles and neurons [71]. Using CPRISPR
ental genes to enhance their expression level and arise a positive knockout strains, the functions of lincRNAs in C. elegans were system-
feedback in genes expression [7]. In addition to the nuclear genome, the atically evaluated by our group, several representative phenotypes were
circular RNAs encoded by mitochondrial genome which are termed as tested in these lincRNAs KO animals, and the global features such as
mecciRNAs also have important roles [8].The mecciRNAs promote their exon numbers, conservation, and length were described [15]. 23
mitochondrial importation of nuclear-encoded proteins, by interacting of 155 KO mutants showed minor abnormalities in locomotion, defe-
with TOM40 and PNPASE serving as molecular chaperones [8]. Dy- cation, pharyngeal pumping, egg retention, development and offspring
namic expression of mecciND1 under stress regulated cellular phy- numbers. Mechanistically, some of these lincRNAs played cis roles to
siology by increasing the RPA70 and RPA32 protein levels in mi- regulate the expression neighboring genes, some of them could function
tochondria [8]. as ceRNAs against microRNAs in trans. By bioinformatics analysis from
ChIP-seq datasets (modENCODE), the 23 phenotypic lincRNAs are
2.3. Other LncRNAs regulated by more transcription factors than the others indicating that
lincRNAs are targets of TFs in neurons to control their function directly
In addition to lincRNAs, there are other forms of lncRNAs which [15,72,73].
modulate cellular physiological functions, such as antisense lncRNAs
and long intronic noncoding RNAs [57–61]. For example, nuclear-en- 3.2. Drosophila melanogaster
riched AS Uchl RNA in dopaminergic neurons upregulates UCHL1
protein levels via the SINEB2 repeat element [57]. The inhibition of Like C. elegans, Drosophila melanogaster is also a kind of classic and
mTORC1 by rapamycin increased UCHL1 protein levels by AS Uchl simple animal model but have more observable phenotypes in genetics
implied a mechanism of antisense lncRNAs in the control of cellular [74–77]. Drosophila is taken as a research platform to investigate the in
stress signaling pathways and their roles in neurodegenerative diseases vivo functions of noncoding RNAs for decades [78–81]. Transcription of
[57]. In other researches, long intronic transcripts take their roles as many Drosophila lncRNAs occurs during embryogenesis and display
precursors of small RNAs, cofactors of alternative promoters and reg- spatiotemporally expression [78]. As a resource study, Wen et al.
ulators of alternative pre-mRNA splicing [58]. Take SAF as an example, identified 128 testis-specific lncRNAs in which 105 of them were
a 1500 nt intronic lncRNA transcribed from the opposite strand of FAS knocked out by CRISPR. Among the KO mutants, only 33 (31%) ex-
gene intron 1 regulates the alternative splicing of FAS in cis to protect hibited male-specific fertility defects most of them (32) just have par-
cells from membrane-mediated apoptosis [59]. In addition, overlapped tially decreased male fertility [82].
transcripts are also involved in cellular events such as 5S-OT(5S rRNA One of the important functions of lncRNAs is to regulate the chro-
overlapped transcript) [60]. 5S-OT modulates 5S rRNA transcription in matin state. LncRNAs involving in the X chromosome dosage compen-
mice and humans by cis effect, and it is intriguing that human 5S-OT sation were elucidated in the studies of Drosophila [83]. RoX1 and roX2
regulates alternative splicing of numerous genes by U2AF65 and Alu genes produce male-specific lncRNAs that co-localize with the MSL
pairing in trans [60]. In a classic human macrophage differentiation (Male-Specific Lethal) protein complex. They form a stable association
model, knockdown of 5S-OT decreased THP-1 cells differentiation ef- with the protein complex and activate the expression of X-linked genes
ficiency [60]. LncRNAs also participate in cell division, for example, in males to equalize genes expression between two sexes [83]. The
171 nt α-satellite RNAs which are transcribed from centromeric repeats ChIRP (Chromatin Isolation by RNA Purification) -seq analysis dis-
are managed by a RNAi pathway and function in chromosome segre- played the Drosophila roX genes binding sites on X chromosome directly
gation [61]. [84]. Interestingly, both roX1 and roX2 are non-essential. Deletion roX1
or roX2 in both sexes had no significant phenotypes [83]. Males of roX
3. The physiological functions of LncRNA in animals double mutants were disrupted in development. Males carrying roX -
chromosomes were lethal and only 5% of them were survival. Although
3.1. Caenorhabditis elegans the double mutant showed the male-specific lethal phenotypes, the
females of them were not affected, either roX1 or roX2 cDNAs could
As simplest one of animal models, Caenorhabditis elegans has many rescue the male-specific phenotypes of the double mutants [83]. At
advantages in genetics and molecular biology researches [62–65]. molecular level, roX1 and roX2 intact with some important proteins
Using C. elegans, researchers found rncs-1, an 800 nt lincRNA(long in- (MSL1-3, MOF, MLE) and form MSL complex to regulate epigenetic
tervening noncoding RNAs) is up-regulated after starvation which is modification such as histone acetylation [85].
expressed in intestine and hypodermis, and inhibits Dicer cleavage in Evidence in Drosophila shows that lncRNAs participate in the cellar
vitro and in vivo [66].Overexpression of rncs-1 led to an increased fre- response to stress. For example, one of the heat shock proteins hsr-
quency of males during starvation indicated its functional roles of omega encoding a nuclear lncRNA, participates in the reorganization of
lncRNAs in response to stress [66]. LncRNAs can regulate development nucleoplasmic omega speckles after heat shock [86]. It functions as a
and sexual maturation. Lep-5, a 600 nt cytoplasmic lincRNA, regulates hub and accumulate hnRNPs. Hsr-omega nullisomic mutants resulted in
developmental timing as a scaffold to bring LEP-2 into its target gene embryonic lethality [86–88]. Recent studies also demonstrated the
LIN-28, and takes part in tail tip morphogenesis of males regulating regulation of lncRNAs in neurogenesis and their molecular mechanism
sexual maturation cell-autonomously in nervous system [67,68]. Lep-5 in flies [89,90]. Neurogenic lncRNAs are expressed specifically during
is conserved across Caenorhabditis uncovering evidence for its function early stages of nervous system development and mark specific subsets
in evolution [67,68]. of neurogenic cell types including neurons and glia [89]. Another study
As model organism which can be handled easily, C. elegans is used in indicated that lncRNAs controlled by Hox genes participated in the
resource research [69]. Using available RNA-seq and other techniques, formation of anteroposterior (AP) axis of Drosophila. A 92k nt lncRNA
170 lincRNAs and 60 ancRNAs(antisense lncRNAs) were identified in C. encoded by the intergenic region isolating Abd-A and Abd-B was
elegans [70]. LincRNAs of C. elegans are expressed in a stage-specific identified [90]. This CNS-specific lincRNA(iab8ncRNA) suppresses the

180
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

expression of Abd-A genes by two redundant mechanisms: the first way mammals is controlled by a long noncoding RNA, Xist [117,118]. It is
is mediated by mir-iab-8, a microRNA encoded by the intronic sequence similar to roX genes in Drosophila, but Xist effects in an opposite way:
within iab8ncRNA; on the other hand, the transcriptional interference roX1 and roX2 activate X-linked genes in males, however Xist inactivate
by iab8ncRNA on Abd-A promoter is involved in the regulation [90].In X-linked genes in females in embryonic development [119–121]. Xist
addition, lncRNAs act not only in the formation and function of nervous RNA can coat and accumulate on one X chromosome (where it is ex-
system but also in the behavior of Drosophila [81,91,92].For instance, pressed), recruit a series of epigenetic regulators then transcriptional
the cytoplasmic yellow-achaete intergenic RNA (yar) which is conserved silencing rapidly ensues [122,123]. Mutations of Xist in mice result in
in Drosophila regulates the sleep behavior, the phenotypic rescue by a females embryonic lethal inheriting paternal allele but males without
yar transgene suggests that it functions in trans [81]. any phenotypes [124,125]. Another lncRNA which was discovered for
several decades is H19, a 2.5 kb untranslated transcript from the distal
3.3. Zebrafish region of chromosome 7 in mice [126]. It is expressed at a very high
level in embryonic tissues including endoderm and mesoderm, and its
Compared to simple models such as nematodes and flies, Danio rerio expression level maintains during several days after birth then dis-
(zebrafish) belongs to vertebrates and is closer to mammals. Zebrafish is appears in adult [117,118]. H19 is an imprinted and exclusive maternal
one of the most classic model vertebrates [93–95]. It has many features origin allele gene [127–129]. The deletion of H19 in mice led to no
such as ease of feeding and embryo transparency that make it an ex- obvious phenotypes except slightly increased growth in homozygous
cellent model for research of developmental biology, stem cell research, mutants [124,129]. For other widely studied lncRNAs, for example,
physiology and toxicology [96–99].LncRNAs of zebrafish were identi- Neat1 and Malat1 are globally expressed and have cellular functions,
fied using RNA deep sequencing approaches in three independent stu- the mutant mice do not exhibit overt abnormalities except for the de-
dies resent years [100]. Ulitsky et al. annotated 567 lincRNAs, by using fects of paraspeckles [130,131]. In another study, the KO mice of Hotair
RNA-seq, ploy(A) mapping and chromatin marks. Among them, only 29 were fertile and viable with slight skeletal abnormalities [132].
had putative mammalian orthologs, but most of them displayed tissue- For the whole organism, there are several lncRNAs which are es-
specific expression [101]. Using MO (morpholino antisense oligos) sential in mammals. In one study, the function of 18 mammalian
knockdown protocol, two conserved lincRNAs exhibited functional lincRNAs candidates were evaluated by mice mutants [22]. 3(Fendrr,
roles and the MO resulted in embryonic defects: Linc-oip5 was required Peril, and Mdgt)of these were critical and the mutants displayed em-
for the normal size of head, eyes and tail; linc-birc6 was required for bryonic and postnatal lethal phenotypes. Fendrr and mdgt might have
brain and eyes development [101]. Pauli et al. performed RNA-seq functions in multiple organs, and Peril might have functions in ESCs
experiments at 8 developmental time points of zebrafish and identified (embryonic stem cells) [22]. However, most of lncRNAs are not es-
lncRNAs expressed during embryogenesis [102]. LncRNAs of zebrafish sential for their loss-of-function mutants are viable and fertile [22,124].
were expressed at lower levels but in narrower time windows compared But on the other hand, they in turn participate in the regulation of many
with coding genes in early embryos and showed tissue-specific and physiological and pathological processes [133,134]. LncRNAs are in-
subcellularly restricted expression patterns [102]. By RNA-seq of 5 volved in pathogen infection [135,136]. For example, Peng et al. re-
different tissues from adult zebrafish, Kaushik et al. annotated 442 ported that the mice infected by SARS-CoV showed significant different
predicted lncRNAs with 419 were newly annotated [103]. 77 lncRNAs expression of lncRNAs which were similar to influenza virus infection
were tissue-specific and the adult brain enriched the most tissue-spe- [135]. LncRNAs are also involved in the cellular responses to bacterial
cific lncRNAs [103]. infection such as Sros1 which could sensitize mice to L. monocytogenes
Some evidence suggests that not only lincRNAs regulate the devel- [136]. LncRNA also play their roles in cancers [137]. Malat-1 is named
opment of zebrafish, but also antisense lncRNAs [102,104,105]. In for its function in metastasis of lung cancer cells, deletion of malat-1 in
zebrafish, an antisense lncRNA, tie-1AS which is expressed spatio- mice impaired tumor cells metastasis. Malat-1 could also be taken as a
temporally can bind tie-1 mRNA selectively to form tie-1: tie-1AS hybrid predictive marker clinically [137]. LncRNAs are involved in metabo-
to regulate tie-1 transcript levels [104]. Overexpression of tie-1AS led to lism [138]. For instance, lipid metabolism regulated by lncRNAs as-
defects in the formation of contact junctions in endothelial cells and sociates with obesity and hepatic steatosis, Muret et al. summarized 60
abnormal vascular development. In addition, tie-1AS is conserved in lncRNAs in mice and humans involved in lipid metabolism and their
humans and mice [104,106]. As vertebrates, zebrafish is used for a functions in diseases [139].Additionally, there is evidence that lncRNAs
model to reveal the conserved functional lncRNAs in humans and their can be regulator in neuroregeneration suggesting their roles in neuro-
roles in diseases [106–108]. The roles of lncRNAs in the regulation of degenerative diseases [140]. Perry et al. reported the lncRNAs ex-
sexual reproduction and behavior were analyzed by Yuan et al. [109]. pressed during neuroregeneration in dorsal root ganglia of mice and
In the brain of zebrafish, there were numerous gender-specific lncRNAs found two key lncRNAs, Silc1 and Norris1 [141]. Silc1 regulated tran-
like humans with 12 new lncRNAs were annotated [109]. Even though scription factor Sox11 in cis, Silc1 KO mice displayed delayed re-
several lncRNAs may be critical and essential in fish, a more recently generation following injury [141].
resource study using CRISPR KO mutants indicated that the majority of
individual lncRNAs in zebrafish had no key roles, and the phenotypes of 4. Summary
the KO mutants such as embryogenesis, viability and fertility had no
overt abnormalities [110]. For cellular physiology, lncRNAs function in proliferation, differ-
entiation, stress, aging, and apoptosis by epigenetic, transcriptional,
3.4. Mammals and post-transcriptional regulation. They can be various forms and play
trans and cis roles in cells [5,10]. The functions and functional me-
The atlas of biological functions of several “star” lncRNAs is chanism of lncRNAs in physiology of animals are revealed using classic
drawing both in vivo and in vitro, using both cultured cells and mam- animal models [62,74,93]. Much evidence exhibits the differences of
malian models such as mice and rats [111–114]. Mus musculus(mouse) their effects between cellular levels and whole organism levels. Even
were usually utilized as a mammalian model in genetics and molecular though lncRNAs show their important roles in many biological pro-
biology for decades [115]. Mice and humans share more than 90% cesses, depletion of them impact fewer phenotypes than expected
conserved regions in the genomes, but in the transcription level, [124]. The resource research using C. elegans, Drosophila and zebrafish
lncRNAs are expressed at a lower level and less conservation in se- suggest that lncRNAs are not essential for whole animal in most cases
quences comparing with coding genes. However, there are thousands of [15,82,110]. Interestingly, the KO mice of many “star” lncRNAs do not
conserved orthologous lncRNAs [116]. The X-chromosome dosage in show obvious phenotypes [18,20,125,129] (Fig. 2). However, lncRNAs

181
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

Fig. 2. LncRNAs Researches in animal models. Advantages and typical cases of lncRNAs researches by different models are listed. In most cases, lncRNAs are not
essential for whole animals.

may play their functional roles under particular physiological and pa- https://doi.org/10.1007/s11427-020-1631-9 Online ahead of print.
thological conditions, making them potential key molecule in organ- [9] M.B. Clark, T.R. Mercer, G. Bussotti, T. Leonardi, K.R. Haynes, et al., Quantitative
gene profiling of long noncoding RNAs with targeted RNA sequencing, Nat.
isms. Methods 12 (4) (2015) 339–342.
[10] J.J. Quinn, H.Y. Chang, Unique features of long non-coding RNA biogenesis and
Declaration of competing interest function, Nat. Rev. Genet. 17 (1) (2016) 47–62.
[11] J. Ponjavic, C.P. Ponting, G. Lunter, Functionality or transcriptional noise?
Evidence for selection within long noncoding RNAs, Genome Res. 17 (5) (2007)
All the authors declared that they have no conflicts of interest to this 556–565.
[12] J.L. Rinn, H.Y. Chang, Genome regulation by long noncoding RNAs, Annu. Rev.
work. We declare that there is no professional or other personal interest Biochem. 81 (2012) 145–166.
of any nature or kind in any product, service and/or company that [13] P.J. Batista, H.Y. Chang, Long noncoding RNAs: cellular address codes in devel-
could be construed as influencing the position presented in, or the re- opment and disease, Cell 152 (6) (2013) 1298–1307.
[14] R.A. Flynn, H.Y. Chang, Long noncoding RNAs in cell-fate programming and re-
view of, the manuscript entitled.
programming, Cell Stem Cell 14 (6) (2014) 752–761.
[15] S. Wei, H. Chen, E.E. Dzakah, B. Yu, X. Wang, T. Fu, et al., Systematic evaluation of
Acknowledgement C. elegans lincRNAs with CRISPR knockout mutants, Genome Biol. 20 (1)
(2019) 7.
[16] R.A. Gupta, N. Shah, K.C. Wang, J. Kim, H.M. Horlings, D.J. Wong, et al., Long
This work was supported by grants to H. C.: the National Natural non-coding RNA HOTAIR reprograms chromatin state to promote cancer metas-
Science Foundation of China (31900442); G. S.: the National Key R&D tasis, Nature 464 (7291) (2010) 1071–1076.
Program of China (2019YFA0802600 and 2018YFC1004500), the [17] J.L. Rinn, M. Kertesz, J.K. Wang, S.L. Squazzo, X. Xu, S.A. Brugmann, et al.,
Functional demarcation of active and silent chromatin domains in human HOX
National Natural Science Foundation of China (31725016, 31930019, loci by noncoding RNAs, Cell 129 (7) (2007) 1311–1323.
and 91940303). [18] A.R. Amandio, A. Necsulea, E. Joye, B. Mascrez, D. Duboule, Hotair is dispensable
for mouse development, PLoS Genet. 12 (12) (2016) e1006232.
[19] V. Tripathi, J.D. Ellis, Z. Shen, D.Y. Song, Q. Pan, A.T. Watt, S.M. Freier, et al., The
References nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by mod-
ulating SR splicing factor phosphorylation, Mol. Cell. 39 (6) (2010) 925–938.
[1] J.S. Mattick, I.V. Makunin, Non-coding RNA, Hum. Mol. Genet. 15 (2006) 17–29. [20] B. Zhang, G. Arun, Y.S. Mao, Z. Lazar, G. Hung, G. Bhattacharjee, et al., The
[2] S.R. Eddy, Non-coding RNA genes and the modern RNA world, Nat. Rev. Genet. 2 lncRNA Malat1 is dispensable for mouse development but its transcription plays a
(12) (2001) 919–929. cis-regulatory role in the adult, Cell Rep. 2 (1) (2012) 111–123.
[3] L. Ma, V.B. Bajic, Z. Zhang, On the classification of long non-coding RNAs, RNA [21] F.A. Abulwerdi, W. Xu, A.A. Ageeli, M.J. Yonkunas, G. Arun, H. Nam, et al.,
Biol. 10 (6) (2013) 925–933. Selective small-molecule targeting of a triple helix encoded by the long noncoding
[4] T. Ravasi, H. Suzuki, K.C. Pangetal, S. Katayama, M. Furuno, R. Okunishi, et al., RNA, MALAT1, ACS Chem. Biol. 14 (2) (2019) 223–235.
Experimental validation of the regulated expression of large numbers of non- [22] M. Sauvageau, L.A. Goff, S. Lodato, B. Bonev, A.F. Groff, C. Gerhardinger, et al.,
coding RNAs from the mouse genome, Genome Res. 16 (1) (2006) 11–19. Multiple knockout mouse models reveal lincRNAs are required for life and brain
[5] C.P. Ponting, L.P. Oliver, W. Reik, Evolution and functions of long noncoding development, Elife 2 (2013) e01749.
RNAs, Cell 136 (4) (2009) 629–641. [23] A. Fujimoto, M. Furuta, Y. Totoki, T. Tsunoda, M. Kato, Y. Shiraishi, et al., Whole-
[6] M.A. Jeffries, Osteoarthritis year in review 2018: genetics and epigenetics, genome mutational landscape and characterization of noncoding and structural
Osteoarthritis Cartilage 27 (3) (2019) 371–377. mutations in liver cancer, Nat. Genet. 48 (5) (2016) 500–509.
[7] Z. Li, C. Huang, C. Bao, L. Chen, M. Lin, L. Dai, et al., Exon-intron circular RNAs [24] J.N. Hutchinson, A.W. Ensminger, C.M. Clemson, C.R. Lynch, J.B. Lawrence,
regulate transcription in the nucleus, Nat. Struct. Mol. Biol. 22 (3) (2005) A. Chess, A screen for nuclear transcripts identifies two linked noncoding RNAs
256–364. associated with SC35 splicing domains, BMC Genom. 8 (2007) 39.
[8] X. Liu, X. Wang, J. Li, S. Hu, Y. Deng, H. Yin, et al., Identification of mecciRNAs [25] C.M. Clemson, J.N. Hutchinson, S.A. Sara, A.W. Ensminger, A.H. Fox, A. Chess,
and their roles in the mitochondrial entry of proteins, Sci. China Life Sci. (2020), et al., An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential

182
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

for the structure of paraspeckles, Mol. Cell. 33 (6) (2009) 717–726. non-coding antisense RNA controls Uchl1 translation through an embedded
[26] L. Standaert, C. Adriaens, E. Radaelli, K.A. Van, C. Blanpain, T. Hirose, et al., The SINEB2 repeat, Nature 491 (7424) (2012) 454–457.
long noncoding RNA Neat1 is required for mammary gland development and [58] R. Louro, A.S. Smirnova, S. Verjovski-Almeida, Long intronic noncoding RNA
lactation, RNA 20 (12) (2014) 1844–1849. transcription: expression noise or expression choice? Genomics 93 (4) (2009)
[27] Y. Cui, G. Li, X. Zhang, F. Dai, R. Zhang, Increased MALAT1 expression contributes 291–298.
to cisplatin resistance in non-small cell lung cancer, Oncol. Lett. 16 (4) (2018) [59] M. Yan, C. Hong, G. Lai, A. Cheng, Y. Lin, S. Chuang, Identification and char-
4821–4828. acterization of a novel gene Saf transcribed from the opposite strand of Fas, Hum.
[28] A.H. Fox, Y.W. Lam, A.K. Leung, C.E. Lyon, J. Andersen, M. Mann, et al., Mol. Genet. 14 (11) (2005) 1465–1474.
Paraspeckles: a novel nuclear domain, Curr. Biol. 12 (1) (2002) 13–25. [60] S. Hu, X. Wang, G. Shan, Insertion of an Alu element in a lncRNA leads to primate-
[29] G.J. Faulkner, Y. Kimura, C.O. Daub, S. Wani, C. Plessy, K.M. Irvine, et al., The specific modulation of alternative splicing, Nat. Struct. Mol. Biol. 23 (11) (2016)
regulated retrotransposon transcriptome of mammalian cells, Nat. Genet. 41 (5) 1011–1019.
(2009) 563–567. [61] C. Huang, X. Wang, X. Liu, S. Cao, G. Shan, RNAi pathway participates in chro-
[30] R. Kogo, T. Shimamura, K. Mimori, K. Kawahara, S. Imoto, T. Sudo, et al., Long mosome segregation in mammalian cells, Cell Discov 1 (2015) 15029.
noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification [62] S. Brenner, The genetics of Caenorhabditis elegans, Genetics 77 (1) (1974) 71–94.
and is associated with poor prognosis in colorectal cancers, Canc. Res. 71 (20) [63] J.E. Sulston, S. Brenner, The DNA of Caenorhabditis elegans, Genetics 77 (1)
(2011) 6320–6326. (1974) 95–104.
[31] M.C. Tsai, O. Manor, Y. Wan, N. Mosammaparast, J.K. Wang, F. Lan, et al., Long [64] A. Fire, S. Xu, M.K. Montgomery, S.A. Kostas, S.E. Driver, C. C Mello, Potent and
noncoding RNA as modular scaffold of histone modification complexes, Science specific genetic interference by double-stranded RNA in Caenorhabditis elegans,
329 (5992) (2010) 689–693. Nature 391 (6669) (1998) 806–811.
[32] P. Schorderet, D. Duboule, Structural and functional differences in the long non- [65] H. Liu, X. Wang, H. Wang, J. Wu, J. Ren, L. Meng, et al., Escherichia coli non-
coding RNA hotair in mouse and human, PLoS Genet. 7 (5) (2011) e1002071. coding RNAs can affect gene expression and physiology of Caenorhabditis elegans,
[33] T. Hung, H.Y. Chang, Long noncoding RNA in genome regulation: prospects and Nat. Commun. 3 (2012) 1073.
mechanisms, RNA Biol. 7 (5) (2010) 582–585. [66] S. Hellwig, B.L. Bass, A starvation-induced noncoding RNA modulates expression
[34] N. Dimitrova, J.R. Zamudio, R.M. Jong, D. Soukup, R. Resnick, K. Sarma, et al., of Dicer-regulated genes, Proc. Natl. Acad. Sci. U.S.A. 105 (35) (2008)
LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and 12897–12902.
to enforce the G1/S checkpoint, Mol. Cell. 54 (5) (2014) 777–790. [67] K.C. Kiontke, R.A. Herrera, E. Vuong, J. Luo, E.M. Schwarz, D.H.A. Fitch, et al.,
[35] S. Loewer, M.N. Cabili, M. Guttman, Y.H. Loh, K. Thomas, I.H. Park, et al., Large The long non-coding RNA lep-5 promotes the Juvenile-to-Adult transition by de-
intergenic non-coding RNA-RoR modulates reprogramming of human induced stabilizing LIN-28, Dev. Cell 49 (4) (2019) 542–555.
pluripotent stem cells, Nat. Genet. 42 (12) (2010) 1113–1117. [68] H. Lawson, E. Vuong, R.M. Miller, K. Kiontke, D.H. Fitch, D.S. Portman, The
[36] M. Guttman, J. Donaghey, B.W. Carey, M. Garber, J.K. Grenier, Glen Munson, Makorin lep-2 and the lncRNA lep-5 regulate lin-28 to schedule sexual maturation
et al., LincRNAs act in the circuitry controlling pluripotency and differentiation, of the C. elegans nervous system, Elife 8 (2019) e43660.
Nature 477 (7364) (2011) 295–300. [69] L. Frezal, M.A. Felix, C. elegans outside the petri dish, Elife 4 (2015) e05849.
[37] M.K. Atianand, W. Hu, A.T. Satpathy, Y. Shen, E.P. Ricci, J.R. Alvarez-Dominguez, [70] J.W. Nam, D.P. Bartel, Long noncoding RNAs in C. Elegans, Genome Res. 22 (12)
et al., A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to re- (2012) 2529–2540.
strain inflammation, Cell 165 (7) (2016) 1672–1685. [71] W. Liu, E. Yu, S. Chen, X. Ma, Y. Lu, X. Liu, Spatiotemporal expression profiling of
[38] M.T. Hsu, M. Coca-Prados, Electron microscopic evidence for the circular form of long intervening noncoding RNAs in Caenorhabditis elegans, Sci. Rep. 7 (1) (2017)
RNA in the cytoplasm of eukaryotic cells, Nature 280 (5720) (1979) 339–340. 5195.
[39] A.C. Arnberg, G.J. van Ommen, L.A. Grivell, E.F. Van Bruggen, P. Borst, et al., [72] B. Yu, X. Wang, S. Wei, T. Fu, E.E. Dzakah, A. Waqas, et al., Convergent tran-
Some yeast mitochondrial RNAs are circular, Cell 19 (2) (1980) 313–319. scriptional programs regulate cAMP levels in C. elegans GABAergic motor neu-
[40] B. Capel, A. Swain, S. Nicolis, A. Hacker, M. Walter, P. Koopman, et al., Circular rons, Dev. Cell 43 (2) (2017) 212–226.
transcripts of the testis-determining gene Sry in adult mouse testis, Cell 73 (5) [73] K. Howell, J.G. White, O. Hobert, Spatiotemporal control of a novel synaptic or-
(1993) 1019–1030. ganizer molecule, Nature 523 (7558) (2015) 83–87.
[41] W.R. Jeck, J.A. Sorrentino, K. Wang, M.K. Slevin, C.E. Burd, J. Liu, et al., Circular [74] W.E. Castle, Inbreeding, cross-breeding and sterility in Drosophila, Science 23
RNAs are abundant, conserved, and associated with ALU repeats, RNA 19 (2) (578) (1906) 153.
(2013) 141–157. [75] T.H. Morgan, Sex limited inheritance in Drosophila, Science 32 (812) (1910)
[42] C.Y. Yu, H.J. Liu, L.Y. Hung, H.C. Kuo, T.J. Chuang, Is an observed non-co-linear 120–122.
RNA product spliced in trans, in cis or just in vitro? Nucleic Acids Res. 42 (14) [76] J.D. Levine, P. Funes, H.B. Dowse, J.C. Hall, Signal analysis of behavioral and
(2014) 9410–9423. molecular cycles, BMC Neurosci. 3 (2002) 1.
[43] S. Umekage, Y. Kikuchi, Production of circular streptavidin RNA aptamer in vivo, [77] J.L. Imler, J.A. Hoffmann, Toll signaling: the TIReless quest for specificity, Nat.
Nucleic Acids Symp. Ser. (51) (2007) 391–392. Immunol. 4 (2) (2003) 105–106.
[44] J. Salzman, R.E. Chen, M.N. Olsen, P.L. Wang, P.O. Brown, Cell-type specific [78] J.L. Tupy, A.M. Bailey, G. Dailey, M. Evans-Holm, C.W. Siebel, S. Misra, et al.,
features of circular RNA expression, PLoS Genet. 9 (9) (2013) e1003777. Identification of putative noncoding polyadenylated transcripts in Drosophila
[45] L.S. Kristensen, M.S. Andersen, L.V.W. Stagsted, K.K. Ebbesen, T.B. Hansen, melanogaster, Proc. Natl. Acad. Sci. U.S.A. 102 (15) (2005) 5495-5000.
J. Kjems, The biogenesis, biology and characterization of circular RNAs, Nat. Rev. [79] A.T. Willingham, S. Dike, J. Cheng, J.R. Manak, I. Bell, E. Cheung, et al.,
Genet. 20 (11) (2019) 675–691. Transcriptional landscape of the human and fly genomes: nonlinear and multi-
[46] Y. Zhang, X. Zhang, T. Chen, J. Xiang, Q. Yin, Y. Xing, et al., Circular intronic long functional modular model of transcriptomes, Cold Spring Harbor Symp. Quant.
noncoding RNAs, Mol. Cell. 51 (6) (2013) 792–806. Biol. 71 (2006) 101–110.
[47] T.B. Hansen, T.I. Jensen, B.H. Clausen, J.B. Bramsen, B. Finsen, C.K. Damgaard, [80] B.R. Graveley, A.N. Brooks, J.W. Carlson, M.O. Duff, J.M. Landolin, L. Yang, et al.,
et al., Natural RNA circles function as efficient microRNA sponges, Nature 495 The developmental transcriptome of Drosophila melanogaster, Nature 471 (7339)
(7441) (2013) 384–388. (2011) 473–479.
[48] Y. Tay, J. Rinn, P.P. Pandolfi, The multilayered complexity of ceRNA crosstalk and [81] A.A. Soshnev, H. Ishimoto, B.F. McAllister, X. Li, M.D. Wehling, T. Kitamoto, et al.,
competition, Nature 505 (7483) (2014) 344–352. A conserved long noncoding RNA affects sleep behavior in drosophila, Genetics
[49] S. Memczak, M. Jens, A. Elefsinioti, F. Torti, J. Krueger, A. Rybak, et al., Circular 189 (2) (2011) 455–468.
RNAs are a large class of animal RNAs with regulatory potency, Nature 495 (7441) [82] K. Wen, L. Yang, T. Xiong, C. Di, D. Ma, M. Wu, Critical roles of long noncoding
(2013) 333–338. RNAs in Drosophila spermatogenesis, Genome Res. 26 (9) (2016) 1233–1244.
[50] J.U. Guo, V. Agarwal, H. Guo, D. P Bartel, Expanded identification and char- [83] V.H. Meller, B.P. Rattner, The roX genes encode redundant male-specific lethal
acterization of mammalian circular RNAs, Genome Biol. 15 (7) (2014) 409. transcripts required for targeting of the MSL Complex, EMBO J. 21 (5) (2002)
[51] D. Barbagallo, A. Condorelli, M. Ragusa, L. Salito, M. Sammito, B. Banelli, et al., 1084–1091.
Dysregulated miR-671-5p/CDR1-AS/CDR1/VSNL1 axis is involved in glio- [84] C. Chu, K. Qu, F.L. Zhong, S.E. Artandi, H.Y. Chang, Genomic maps of long non-
blastoma multiforme, Oncotarget 7 (4) (2016) 4746–4759. coding RNA occupancy reveal principles of RNA-chromatin interactions, Mol. Cell.
[52] M. Piwecka, P. Glažar, L.R. Hernandez-Miranda, S. Memczak, S.A. Wolf, A. Rybak- 44 (4) (2011) 667–678.
Wolf, et al., Loss of a mammalian circular RNA locus causes miRNA deregulation [85] T. Chelmicki, F. Dündar, M.J. Turley, T. Khanam, T. Aktas, F. Ramírez, et al., MOF-
and affects brain function, Science 357 (6357) (2017) eaam8526. associated complexes ensure stem cell identity and Xist repression, Elife 3 (2014)
[53] H. Xu, S. Guo, W. Li, P. Yu, The circular RNA Cdr1as, via miR-7 and its targets, e02024.
regulates insulin transcription and secretion in islet cells, Sci. Rep. 5 (2015) [86] K.V. Prasanth, T.K. Rajendra, A.K. Lal, S.C. Lakhotia, Omega Speckles - a novel
12453. class of nuclear speckles containing hnRNPs associated with noncoding Hsr-
[54] L. Yu, X. Gong, L. Sun, Q. Zhou, B. Lu, L. Zhu, The circular RNA Cdr1as act as an Omega RNA in Drosophila, J. Cell Sci. 113 (Pt 19) (2000) 3485–3497.
oncogene in hepatocellular carcinoma through targeting miR-7 expression, PloS [87] T.K. Rajendra, K.V. Prasanth, S. C Lakhotia, Male sterility associated with over-
One 11 (7) (2016) e0158347. expression of the noncoding Hsromega gene in cyst cells of testis of Drosophila
[55] P. Xia, S. Wang, B. Ye, Y. Du, C. Li, Z. Xiong, A circular RNA protects dormant melanogaste, J. Genet. 80 (2) (2001) 97–110.
hematopoietic stem cells from DNA sensor cGAS-mediated exhaustion, Immunity [88] M. Mallik, S.C. Lakhotia, Improved activities of CREB binding protein, hetero-
48 (4) (2018) 688–701. geneous nuclear ribonucleoproteins and proteasome following downregulation of
[56] W.W. Du, W. Yang, E. Liu, Z. Yang, P. Dhaliwal, B.B. Yang, Foxo3 circular RNA noncoding Hsromega transcripts help suppress poly(Q) pathogenesis in fly models,
retards cell cycle progression via forming ternary complexes with p21 and CDK2, Genetics 184 (4) (2010) 927–945.
Nucleic Acids Res. 44 (6) (2016) 2846–2858. [89] A.L. McCorkindale, P. Wahle, S. Werner, I. Jungreis, P. Menzel, C.J. Shukla, A gene
[57] C. Carrieri, L. Cimatti, M. Biagioli, A. Beugnet, S. Zucchelli, S. Fedele, et al., Long expression atlas of embryonic neurogenesis in Drosophila reveals complex

183
H. Chen and G. Shan Non-coding RNA Research 5 (2020) 178–184

spatiotemporal regulation of lncRNAs, Development 146 (6) (2019) dev175265. [116] A.I. Su, M.P. Cooke, K.A. Ching, Y. Hakak, J.R. v, T. Wiltshire, et al., Large-scale
[90] M. Gummalla, S. Galetti, R.K. Maeda, F. Karch, Hox gene regulation in the central analysis of the human and mouse transcriptomes, Proc. Natl. Acad. Sci. U.S.A. 99
nervous system of Drosophila, Front. Cell. Neurosci. 8 (2014) 96. (7) (2002) 4465–4470.
[91] M. Li, S. Wen, X. Guo, B. Bai, Z. Gong, X. Liu, et al., The novel long non-coding [117] V. Pachnis, C.I. Brannan, S.M. Tilghman, The structure and expression of a novel
RNA CRG regulates Drosophila locomotor behavior, Nucleic Acids Res. 40 (22) gene activated in early mouse embryogenesis, EMBO J. 7 (3) (1988) 673–681.
(2012) 11714–11727. [118] D. Kitsberg, S. Selig, M. Brandeis, I. Simon, I. Keshet, D.J. Driscoll, et al., Allele-
[92] M. Li, L. Liu, Neural functions of long noncoding RNAs in Drosophila, J. Comp. specific replication timing of imprinted gene regions, Nature 364 (6436) (1993)
Physiol. A. 201 (9) (2015) 921–926. 459–463.
[93] G. Streisinger, C. Walker, N. Dower, D. Knauber, F. Singer, Production of clones of [119] N. Brockdorff, A. Ashworth, G.F. Kay, V.M. McCabe, D.P. Norris, P.J. Cooper,
homozygous diploid zebra fish (brachydanio rerio), Nature 291 (5813) (1981) et al., The product of the mouse Xist gene is a 15 kb inactive X-specific transcript
293–296. containing no conserved ORF and located in the nucleus, Cell 71 (3) (1992)
[94] S. Chakrabarti, G. Streisinger, F. Singer, C. Walker, Frequency of gamma-Ray in- 515–522.
duced specific locus and recessive lethal mutations in mature germ cells of the [120] J. Zhao, B.K. Sun, J.A. Erwin, J.J. Song, J.T. Lee, Polycombproteins targeted by a
Zebrafish, BRACHYDANIO RERIO, Genetics 103 (1) (1983) 109–123. short repeat RNA to the mouse X chromosome, Science 322 (5902) (2008)
[95] A. Meyer, C.H. Biermann, G. Orti, The phylogenetic position of the zebrafish 750–756.
(Danio Rerio), a Model system in developmental biology: an invitation to the [121] C.A. McHugh, C.K. Chen, A. Chow, C.F. Surka, C. Tran, P. McDonel, et al., The Xist
comparative method, Proc. Biol. Sci. 252 (1335) (1993) 231–236. lncRNA interacts directly with SHARP to silence transcription through HDAC3,
[96] C.B. Kimmel, Genetics and early development of Zebrafish, Trends Genet. 5 (8) Nature 521 (7551) (2015) 232–236 521.
(1989) 283–288. [122] C. Chu, Q.C. Zhang, S.T. da Rocha, R.A. Flynn, M. Bharadwaj, J.M. Calabrese,
[97] V. Torraca, S. Mostowy, Zebrafish infection: from pathogenesis to cell biology, et al., Systematic discovery of xist RNA binding proteins, Cell 161 (2) (2015)
Trends Cell Biol. 28 (2) (2018) 143–156. 404–416.
[98] L.I. Zon, R.T. Peterson, In vivo drug discovery in the zebrafish, Nat. Rev. Drug [123] B. Czermin, R. Melfi, D. McCabe, V. Seitz, A. Imhof, V. Pirrotta, Drosophila en-
Discov. 4 (1) (2005) 35–44. hancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that
[99] D. Fagegaltier, A. Lescure, R. Walczak, P. Carbon, A. Krol, Structural analysis of marks chromosomal Polycomb sites, Cell 111 (2) (2002) 185–196.
new local features in SECIES RNA hairpins, Nucleic Acids Res. 28 (14) (2000) [124] A.R. Bassett, A. Akhtar, D.P. Barlow, A.P. Bird, N. Brockdorff, D. Duboule, et al.,
2679–2689. Considerations when investigating lncRNA function in vivo, Elife 3 (2014)
[100] S. Haque, K. Kaushik, V.E. Leonard, S. Kapoor, A. Sivadas, A. Joshi, et al., Short e03058.
stories on zebrafish long noncoding RNAs, Zebrafish 11 (6) (2014) 499–508. [125] Y. Marahrens, B. Panning, J. Dausman, W. Strauss, R. Jaenisch, Xist-deficient mice
[101] I. Ulitsky, A. Shkumatava, C.H. Jan, H. Sive, D.P. Bartel, Conserved function of are defective in Dosage Compensation but not spermatogenesis, Genes Dev. 11 (2)
lincRNAs in vertebrate embryonic development despite rapid sequence evolution, (1997) 156–166.
Cell 147 (7) (2011) 1537–1550. [126] C.I. Brannan, E.C. Dees, R.S. Ingram, S.M. Tilghman, The product of the H19 gene
[102] A. Pauli, E. Valen, M.F. Lin, M. Garber, N.L. Vastenhouw, J.Z. Levin, et al., may function as an RNA, Mol. Cell Biol. 10 (1) (1990) 28–36.
Systematic identification of long noncoding RNAs expressed during zebrafish [127] M.V. Koerner, F.M. Pauler, R. Huang, D.P. Barlow, The function of non-coding
embryogenesis, Genome Res. 22 (3) (2012) 577–591. RNAs in genomic imprinting, Development 136 (11) (2009) 1771–1783.
[103] K. Kaushik, V.E. Leonard, S. Kv, M.K. Lalwani, S. Jalali, A. Patowary, et al., [128] T. Thamban, V. Agarwaal, S. Khosla, Role of genomic imprinting in mammalian
Dynamic expression of long non-coding RNAs (lncRNAs) in adult zebrafish, PloS development, J. Biosci. 45 (2020) 20.
One 8 (12) (2013) e83616. [129] M.A. Ripoche, C. Kress, F. Poirier, L. Dandolo, Deletion of the H19 transcription
[104] K. Li, Y. Blum, A. Verma, Z. Liu, K. Pramanik, N.R. Leigh, et al., A noncoding unit reveals the existence of a putative imprinting control element, Genes Dev. 11
antisense RNA in tie-1 locus regulates tie-1 function in vivo, Blood 115 (1) (2010) (12) (1997) 1596–1604.
133–139. [130] S. Nakagawa, T. Naganuma, G. Shioi, T. Hirose, Paraspeckles are subpopulation-
[105] Z. Cheng, Q. Zhang, A. Yin, M. Feng, H. Li, H. Liu, et al., The long non-coding RNA specific nuclear bodies that are not essential in mice, J. Cell Biol. 193 (1) (2011)
uc.4 influences cell differentiation through the TGF-beta signaling pathway, Exp. 31–39.
Mol. Med. 50 (2) (2018) e447. [131] S. Nakagawa, J.Y. Ip, G. Shioi, V. Tripathi, X. Zong, T. Hirose, Malat1 is not an
[106] M. Guttman, I. Amit, M. Garber, C. French, M.F. Lin, D. Feldser, et al., Chromatin essential component of nuclear speckles in mice, RNA 18 (8) (2012) 1487–1499.
signature reveals over a thousand highly conserved large non-coding RNAs in [132] L. Li, B. Liu, O.L. Wapinski, M.C. Tsai, K. Qu, J. Zhang, et al., Targeted disruption
mammals, Nature 458 (7235) (2009) 223–227. of Hotair leads to homeotic transformation and gene derepression, Cell Rep. 5 (1)
[107] S. Basu, F. Müller, R. Sanges, Examples of sequence conservation analyses capture (2013) 3–12.
a subset of mouse long non-coding RNAs sharing homology with fish conserved [133] I. Shamovsky, E. Nudler, Gene control by large noncoding RNAs, Sci. STKE. 2006
genomic elements, BMC Bioinf. 14 (7) (2013) S14. 355 (2006) pe40.
[108] W. Chen, X. Zhang, J. Li, S. Huang, S. Xiang, X. Hu, et al., Comprehensive analysis [134] S. Nakagawa, Lessons from reverse-genetic studies of lncRNAs, Biochim. Biophys.
of coding-lncRNA gene co-Expression network uncovers conserved functional Acta 1859 (1) (2016) 177–183.
lncRNAs in Zebrafish, BMC Genom. 19 (2) (2018) 112. [135] W. Liu, C. Ding, Roles of LncRNAs in viral infections, Front. Cell. Infect. Microbiol
[109] W. Yuan, S. Jiang, D. Sun, Z. Wu, C. Wei, C. Dai, et al., Transcriptome profiling 7 (2016) 205.
analysis of sex-based differentially expressed mRNAs and lncRNAs in the brains of [136] H. Xu, Y. Jiang, X. Xu, X. Su, Y. Liu, Y. Ma, et al., Inducible degradation of lncRNA
mature zebrafish (Danio rerio), BMC Genom. 20 (1) (2019) 830. Sros1 promotes IFN-γ-mediated activation of innate immune responses by stabi-
[110] M. Goudarzi, K. Berg, L.M. Pieper, A.F. Schier, Individual long non-coding RNAs lizing Stat1 mRNA, Nat. Immunol. 20 (12) (2019) 1621–1630.
have no overt functions in zebrafish embryogenesis, viability and fertility, Elife 8 [137] T. Gutschner, M. Hämmerle, M. Eissmann, J. Hsu, Y. Kim, G. Hung, The noncoding
(2019) e40815. RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer
[111] J.A. Briggs, E.J. Wolvetang, J.S. Mattick, J.L. Rinn, G. Barry, Mechanisms of long cells, Canc. Res. 73 (3) (2013) 1180–1189.
non-coding RNAs in mammalian nervous system development, plasticity, disease, [138] P. Wang, J. Xu, Y. Wang, X. Cao, An interferon-independent lncRNA promotes
and evolution, Neuron 88 (5) (2015) 861–877. viral replication by modulating cellular metabolism, Science 358 (6366) (2017)
[112] B.K. Dey, A.C. Mueller, A. Dutta, Long non-coding RNAs as emerging regulators of 1051–1055.
differentiation, development, and disease, Transcription 5 (4) (2014) e944014. [139] K. Muret, C. Désert, L. Lagoutte, M. Boutin, F. Gondret, T. Zerjal, et al., Long
[113] V.A. Moran, R.J. Perera, A.M. Khalil, Emerging functional and mechanistic para- noncoding RNAs in lipid metabolism literature review and conservation analysis
digms of mammalian long non-coding RNAs, Nucleic Acids Res. 40 (14) (2012) across species, BMC Genom. 20 (1) (2019) 882.
6391–6400. [140] A.D. Ramos, F.J. Attenello, D.A. Lim, Uncovering the roles of long noncoding
[114] S. Jain, N. Thakkar, J. Chhatai, M.P. Bhadra, U. Bhadra, Long non-coding RNA: RNAs in neural development and glioma progression, Neurosci. Lett. 625 (2019)
functional agent for disease traits, RNA Biol. 14 (5) (2017) 522–535. 70–79.
[115] V. Azzu, T.G. Valencak, Energy metabolism and ageing in the mouse: a mini-re- [141] R.B. Perry, H. Hezroni, M.J. Goldrich, I. Ulitsky, Regulation of neuroregeneration
view, Gerontology 63 (4) (2017) 327–336. by long noncoding RNAs, Mol. Cell. 72 (3) (2018) 553–567.

184