data

Data Descriptor
Preprocessing of Public RNA-Sequencing Datasets to Facilitate
Downstream Analyses of Human Diseases
Naomi Rapier-Sharman , John Krapohl, Ethan J. Beausoleil, Kennedy T. L. Gifford, Benjamin R. Hinatsu,
Curtis S. Hoffmann, Makayla Komer, Tiana M. Scott and Brett E. Pickett *

Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA;
[email protected] (N.R.-S.); [email protected] (J.K.); [email protected] (E.J.B.);
[email protected] (K.T.L.G.); [email protected] (B.R.H.); [email protected] (C.S.H.);
[email protected] (M.K.); [email protected] (T.M.S.)
* Correspondence: [email protected]

Abstract: Publicly available RNA-sequencing (RNA-seq) data are a rich resource for elucidating the
mechanisms of human disease; however, preprocessing these data requires considerable bioinfor-
matic expertise and computational infrastructure. Analyzing multiple datasets with a consistent
computational workflow increases the accuracy of downstream meta-analyses. This collection of
datasets represents the human intracellular transcriptional response to disorders and diseases such
as acute lymphoblastic leukemia (ALL), B-cell lymphomas, chronic obstructive pulmonary disease
(COPD), colorectal cancer, lupus erythematosus; as well as infection with pathogens including Borrelia
burgdorferi, hantavirus, influenza A virus, Middle East respiratory syndrome coronavirus (MERS-





 CoV), Streptococcus pneumoniae, respiratory syncytial virus (RSV), severe acute respiratory syndrome
coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We
Citation: Rapier-Sharman, N.;
Krapohl, J.; Beausoleil, E.J.; Gifford,
calculated the statistically significant differentially expressed genes and Gene Ontology terms for
K.T.L.; Hinatsu, B.R.; Hoffmann, C.S.; all datasets. In addition, a subset of the datasets also includes results from splice variant analyses,
Komer, M.; Scott, T.M.; Pickett, B.E. intracellular signaling pathway enrichments as well as read mapping and quantification. All analyses
Preprocessing of Public RNA- were performed using well-established algorithms and are provided to facilitate future data mining
Sequencing Datasets to Facilitate activities, wet lab studies, and to accelerate collaboration and discovery.
Downstream Analyses of Human
Diseases. Data 2021, 6, 75. https:// Dataset: https://zenodo.org/record/4757764; DOI:10.5281/zenodo.4757764.
doi.org/10.3390/data6070075

Dataset License: CC-BY.

Academic Editor: Ralph A. Tripp

Keywords: transcriptomics; RNA-sequencing; autoimmune diseases; cancer; pathogens; bacteria;

Received: 8 June 2021
viruses; data preprocessing
Accepted: 12 July 2021
Published: 15 July 2021

Publisher’s Note: MDPI stays neutral

1. Summary
with regard to jurisdictional claims in
published maps and institutional affil- The number of publicly available RNA-sequencing (RNA-seq) datasets is increasing,
iations. and we expect this momentum to continue. However, comprehensive results from statisti-
cal analyses such as differential gene expression are not consistently available in public
transcriptomics repositories such as the Gene Expression Omnibus (GEO). Additionally,
in the subset of cases where multiple differentially expressed gene (DEG) lists from dif-
Copyright: © 2021 by the authors.
ferent experiments are available, directly comparing them is difficult due to the differing
Licensee MDPI, Basel, Switzerland.
parameters, assumptions, and biases present within each of the preprocessing algorithms
This article is an open access article
(e.g., trimming, mapping, quantification; see sampling of pipelines and methods) [1–5].
distributed under the terms and A survey of the literature confirms that transcriptomic preprocessing pipelines utilize a
conditions of the Creative Commons variety of underlying statistical models, further complicating comparison between two
Attribution (CC BY) license (https:// datasets processed by different pipelines.
creativecommons.org/licenses/by/ Our motivation for publishing these preprocessed public datasets was to make the
4.0/). results from these computational methods accessible to facilitate hypothesis generation, as

Data 2021, 6, 75. https://doi.org/10.3390/data6070075 https://www.mdpi.com/journal/data

Data 2021, 6, 75 2 of 10

well as for subsequent analysis and interpretation by researchers. In particular, to aid those
who may not have the necessary computational infrastructure or expertise to perform this
work. The specialized bioinformatic expertise required to successfully preprocess and
analyze RNA-seq data can pose a significant barrier for some research groups. To complete
an RNA-seq analysis, researchers must find relevant studies, collect the necessary metadata,
quantify read mapping, calculate the DEGs, perform Gene Ontology (GO) enrichment,
and compute significant signaling pathways. In addition, it is not uncommon to read and
write over one terabyte of data while completing a large meta-analysis, which can exceed
the computational capacity available to some researchers. The results from preprocessing
and analyzing datasets such as those presented in the current study can save researchers
both time and resources by easily retrieving genes, biological functions, pathways, and/or
splice variants that are significantly affected during a given disease or condition. These
biological entities could be further evaluated to identify potential biomarkers and disease
mechanisms that can be exploited to improve diagnosis or treatment of disease, and to
increase the speed of research in these fields.
Although the scope of the current study is to report the results of various computa-
tional methods on public datasets, we are unable to accurately interpret the data in all of
the pathologies for which we have preprocessed data. This makes it imperative that the
research community reviews the genes, functions, and pathways that were identified.
Combining multiple individual datasets in a meta-analysis increases the statistical
power of the derived results by increasing the signal-to-noise ratio. Multiple previous
studies have shown that removing background noise makes it easier to gain additional
insight on the underlying biological mechanisms that play a role in any given system [6–8].
Specific examples of prior meta-analyses that revealed novel results from existing data
include Kori and Arga identifying 18 previously unknown cervical cancer receptors [9],
Patel et al. discovering that the accepted transcriptional profile of Alzheimer’s disease only
applies to the temporal lobe, with distinct gene expression patterns appearing in other
areas of the Alzheimer’s-diseased brain [10], and Zhang et al. finding evidence that CD-38,
LAG-3, and interferon-1 stimulated genes are linked to the progression to AIDS after HIV
infection [11].
The goal of the current study was to produce lists of DEGs and GO terms for each target
dataset together with statistically significant splice variants, and signaling pathways, and
quantification results for subsequent analysis and interpretation by the research community.
We used the ARMOR automated analytical workflow as well as custom scripts to preprocess
and analyze samples across various targeted infectious diseases as well as other human
diseases and conditions. For infectious diseases, we queried for samples quantifying the
host response to Borrelia burgdorferi, hantavirus, influenza A virus, MERS, respiratory
syncytial virus, Streptococcus pneumoniae, SARS-CoV, and SARS-CoV-2. We also targeted
non-infectious diseases and conditions that include acute lymphoblastic leukemia, B-
cell lymphomas, chronic obstructive pulmonary disease, colorectal cancer, and lupus
erythematosus. Our primary focus was on datasets from humans or human-derived
cell lines, with a small number of datasets from mice or murine cell lines. Providing
consistently preprocessed RNA-seq datasets for secondary analysis and research minimizes
the bioinformatics barrier, enabling researchers to perform preliminary and/or in depth in
silico analyses.
The public availability of these analytical results supports the findable, accessible,
interoperable, and reusable (FAIR) guidelines [12]. Our study preprocessed the raw data
from 31 public datasets and makes the results from each publicly available. We are not
aware of any prior report that contributes the results from such a large number of prepro-
cessed RNA-seq datasets in a single study. Unfortunately, some meta-analyses that have
been performed only report cherry-picked genes and pathways from the DEG list and
do not consistently publish the complete lists of genes, functions, and/or pathways that
were generated during the meta-analysis. Though we do not provide a comprehensive
interpretation of these preprocessed results in this study, the files that were generated
Data 2021, 6, 75 3 of 10

by this study contain lists from which additional downstream work can be done. In an
attempt to provide some validation to our work, we have included several examples from
published research that support the results from our preprocessing workflow. We expect
that our efforts to compile and preprocess these datasets will fuel future experiments to
develop novel targeted diagnostics and/or treatments.

2. Data Description
The initial component of this data processing workflow required the manual searching
and curation of appropriate metadata associated with each study to better inform our
analytical design. Although this metadata review process was labor intensive, we believe
it augments the value of the results. As such, we greatly appreciate the existing minimal
information standards for Minimum Information about a Next-Generation Sequencing
Experiment (MINSEQE) and Minimum Information for Biological and Biomedical Inves-
tigations (MIBBI) [13]. We highly recommend continued improvement and adherence to
such standards.
Overall, we preprocessed and analyzed 31 datasets consisting of over 1250 samples
(Table 1). The results from these analyses are reported in over 200 files that contain
significant changes in gene expression (EdgeR files), Gene Ontology terms (Camera files),
splice variants (DRIMSeq files), intracellular signaling pathways (SPIA files), and/or
read mapping/quantification (Salmon files). We estimate that this work required over 25
terabytes of data being read and written throughout the workflow, hundreds of person-
hours, and thousands of CPU-hours to complete.
We have provided a few examples of genes identified as significant by our analysis
which have been reported in prior studies. We include these to validate the accuracy of our
approach and to reiterate the value that these data contain.
For the DEG analysis of pre-treatment Borrelia burgdorferi infection vs. healthy controls,
several of the top 10 significant DEGs identified in the current study have been previously
associated with Lyme disease. Specifically, CoQ10 was shown to be an effective supplemen-
tal treatment for chronic Lyme Disease patients’ fatigue [14], suggesting that the blockage
of CoQ10A, a gene which had a log2 fold change (logFC) of −1.8 and a false-discovery
rate-corrected p-value (FDR) of 1.22 × 10−12 in our results, could be a pathogenic mecha-
nism of B. burgdorferi. Though no direct connection has been made between B. burgdorferi
and LEMD3, a rheumatology review considered both LEMD3 mutation and B. burgdorferi
infection as sources of painful, scleroderma-like disorders [15]. This indicates that the
classic Lyme disease symptom of joint pains may originate from the downregulation of
LEMD3 (logFC = −1.68, FDR = 1.31 × 10−12 ) during infection. Mutations in C19orf12
result in hereditary neuropathies of paraspasticity and Silver Syndrome [16], suggesting
that the neuropathic symptoms of B. burgdorferi infection may result at least partially from
the downregulation of C19orf12 (logFC = −2.6, FDR = 1.20 × 10−11 ).
Our results for Respiratory Syncytial Virus (RSV) identified a handful of gene products
that are suspected to be critical to the patient response during RSV infection. Specifically,
González-Sanz et al. demonstrated that interferon-stimulated gene 15 (ISG15; logFC = 4.2,
FDR = 3.20 × 10−41 ) has a strong anti-viral effect in vitro and suggest that the same effects
may be part of the human innate immune response in vivo [17]. IFIT1 (logFC = 5.04, FDR
= 6.54 × 10−40 ), IFIT2 (logFC = 4.78, FDR = 5.85 × 10−39 ), and IFIT3 (logFC = 4.87, FDR =
4.92 × 10−39 ) are all proteins that have an anti-viral effect on RSV [18], indicating that their
upregulation during infection is likely a protective measure against the virus. During viral
infections, PARP9 (logFC = 2.99, FDR = 1.45 × 10−38 ) and DTX3L (logFC = 2.21, FDR = 9.92
× 10−27 ) form a complex to induce interferon hyper-responsiveness without toxicity [19].
Our B-cell lymphoma preprocessed dataset also yielded DEGs that have been identi-
fied in previous wet-lab experiments. CXCL9 (logFC = 11, FDR = 4.31 × 10−141 ) has been
shown to promote the progression of diffuse large B-cell lymphoma by starting a cascade
that upregulates oncogenes such as CCND1 (logFC = 2.23, FDR = 1.08 × 10−22 ) [20]. Upreg-
ulated VCAM1 (logFC = 7.85, FDR = 2.29 × 10−120 ) is associated with a poor prognosis for
Data 2021, 6, 75 4 of 10

patients with non-Hodgkin’s lymphomas and is under investigation as a serum biomarker

for disease progression assessment [21].
Due to the varying origins of the RNA-sequencing data we preprocessed, our results
may contain background noise that potentially reflects laboratory artifacts, differences
in protocols, or other biases. Although human error is also a possibility, meta-analyses
generally reduce the statistical “noise” of outlier samples by “drowning them out” by
including large numbers of samples in the process. We also performed quality control
on the sample data before any statistical analysis was started. Additionally, our chosen
bioinformatic workflow implements a false-discovery rate (FDR) multiple hypothesis
correction on all initial p-values, effectively reducing the occurrence of false-positives.
Overall, we feel that the impact of any noise or error on our statistical analyses has been
minimized.
The statistically significant findings from each of these datasets could be further
analyzed by performing Boolean comparisons of DEGs, GO terms, and pathways. Such
an analysis would identify entities that are unique to a given dataset or shared between
multiple datasets. The results from such meta-analyses could then be used to generate
testable hypotheses and design robust validation experiments in the wet lab. The data
generated in this work can facilitate more in-depth data mining activities that enable
biomarker identification, improving understanding of disease, and the repurposing of
existing drugs. We anticipate that making these preprocessed RNA-seq datasets publicly
available will ensure that scientific data remains findable, accessible, interoperable, and
reusable (FAIR), while simultaneously fueling collaboration, innovation, and discovery.
Data 2021, 6, 75 5 of 10

Table 1. Summary of preprocessed datasets.

EdgeR, Camera,
Disease/Disorder Organism Tissue Type Sample Type # of Studies # of Samples GEO Identifier Salmon SPIA
DRIMseq
Acute Lymphoblastic Blood and bone
Homo sapiens Total RNA 1 10 GSE162894 [22] Yes Yes Yes
Leukemia (ALL) marrow
GSE153437 [23]
GSE130751 [24]
GSE110219 [25]
B-cell Lymphomas Homo sapiens B-cells mRNA 7 322 GSE95013 [26] Yes Yes Yes
GSE62241 [27]
GSE50514 [28]
GSE45982 [29]
Borrelia burgdorferi Homo sapiens PBMC mRNA 1 97 GSE63085 [30] Yes Yes No
Chronic Obstructive
Homo sapiens Lung tissue mRNA 1 189 GSE57148 [31] Yes No No
Pulmonary Disease (COPD)
GSE104836 [32]
Colorectal cancer Homo sapiens Colorectal tissue lncRNA 3 44 GSE124526 [33] Yes Partial Yes
GSE155457 [34]
GSE133751 [35]
Hantavirus Homo sapiens PBMC, HUVEC Total RNA 2 36 Yes No Yes
GSE158712 [36]
Influenza A Homo sapiens A549 mRNA 1 4 GSE147507 [37] Yes No Yes
GSE92387 [38]
Lupus Erythematosus Homo sapiens B-cells mRNA 3 335 GSE118254 [39] Yes Yes Yes
GSE110999 [40]
Middle East Respiratory GSE139516 [41]
Syndrome Coronavirus Homo sapiens Calu-3 mRNA 3 31 GSE122876 [42] Yes Partial Yes
(MERS-CoV) GSE56192 1
GSE150811 1
Nasal samples, nasal
GSE79595 [43]
Homo sapiens, lavage, Total RNA,
Streptococcus pneumoniae 5 104 GSE116604 [44] Yes Yes Yes
Mus Musculus polymorphonuclear mRNA
GSE117580 [45]
leukocytes, A549
GSE124949 [46]
Data 2021, 6, 75 6 of 10

Table 1. Cont.

EdgeR, Camera,
Disease/Disorder Organism Tissue Type Sample Type # of Studies # of Samples GEO Identifier Salmon SPIA
DRIMseq
Respiratory syncytial virus
Homo sapiens A549 mRNA 1 4 GSE147507 [37] Yes No Yes
(RSV)
Severe acute respiratory
syndrome coronavirus Homo sapiens MRC5 Total RNA 1 15 GSE56192 1 Yes No Yes
(SARS-CoV)
A549, NHBE, Calu-3, GSE147507 [37]
Severe acute respiratory
RUES2-derived lung mRNA, GSE149312 [47]
syndrome coronavirus 2 Homo sapiens 4 38 Yes Yes Yes
cells, M1 + M2 scRNA GSE150708 [48]
(SARS-CoV2)
macrophages GSE153970 [49]
1 No published study is currently associated with this dataset on NCBI’s GEO.
Data 2021, 6, 75 7 of 10

3. Methods
The raw data for these experiments have been previously released by the primary
authors and conform to the appropriate ethical oversight to protect patient autonomy
and patient identity. Thirty of the 33 primary RNA-sequencing datasets from which we
gathered samples for meta-analysis have been published in the peer-reviewed literature,
increasing overall confidence that each dataset has acceptable quality.
GEO queries were used to identify all of the relevant publicly available RNA-seq
experiments data from NCBI for each targeted condition. Samples involving drug ex-
periments, treatments, xenografts, irrelevant tissue type, irrelevant disease, or otherwise
unrelated to our disease vs. healthy comparisons were excluded. All samples that had
one or more of these disqualifying attributes were excluded from the dataset prior to our
analysis, meaning that only a subset of the samples from an individual experiment were
represented in our meta-analyses. Healthy control samples were obtained from the same
RNA sequencing projects as the disease samples.
Fastq sequencing files were downloaded from the Sequence Read Archive (SRA)
using sratools. The fastq files, the associated metadata, and a configuration file for each
dataset were then used as input to the Automated Reproducible MOdular Workflow for
Preprocessing and Differential Analysis of RNA-seq Data (ARMOR) workflow [50]. This
workflow uses a configuration file to appropriately set up each python-based snakemake
workflow [51]. Specifically, this workflow trims reads with TrimGalore! [52], calculates
quality control metrics with FastQC [53], maps and quantifies reads to the human GRCh38
transcriptome with Salmon [54], generates DEG lists with edgeR [55], performs GO en-
richment with Camera [56], and calculates significant splice variants with DRIMseq [57].
Together, TrimGalore! and FastQC ensure that only the high-quality regions of sequences
are considered in the statistical analyses performed by downstream modules, and that the
quality of the included regions can be manually confirmed by the researcher at any point
during the analysis. The DEGs from the ARMOR workflow were then used as input to an R
script that implements the signaling pathway impact analysis (SPIA) algorithm to identify
intracellular signaling pathways that were significantly represented by the DEGs [58].

Author Contributions: Conceptualization, B.E.P.; methodology, B.E.P.; formal analysis, N.R.-S., J.K.,
E.J.B., K.T.L.G., B.R.H., C.S.H., M.K., T.M.S. and B.E.P.; investigation, N.R.-S., J.K., E.J.B., K.T.L.G.,
B.R.H., C.S.H., M.K., T.M.S. and B.E.P.; writing—original draft preparation, N.R.-S.; writing—review
and editing, N.R.-S., J.K. and B.E.P.; supervision, B.E.P. All authors have read and agreed to the
published version of the manuscript.
Funding: We thank the BYU College of Life Sciences for providing the resources necessary to
complete this work. This research received no external funding.
Institutional Review Board Statement: Ethical review and approval were waived for this study, due
to the public availability of included datasets.
Informed Consent Statement: Patient consent was waived due to the datasets already being publicly
available.
Data Availability Statement: The data we have announced in this publication is available for
download online at Zenodo: https://zenodo.org/record/4757764, DOI:10.5281/zenodo.4757764.
Acknowledgments: We thank the high-performance computing resources provided by the BYU
Research Computing Center. We also gratefully acknowledge those who generated, provided, and
submitted the original data.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
Data 2021, 6, 75 8 of 10

References
1. Ma, T.; Huo, Z.; Kuo, A.; Zhu, L.; Fang, Z.; Zeng, X.; Lin, C.-W.; Liu, S.; Wang, L.; Liu, P.; et al. MetaOmics: Analysis Pipeline and
Browser-Based Software Suite for Transcriptomic Meta-Analysis. Bioinformatics 2019, 35, 1597–1599. [CrossRef]
2. Wang, H.-Q.; Zheng, C.-H.; Zhao, X.-M. JNMFMA: A Joint Non-Negative Matrix Factorization Meta-Analysis of Transcriptomics
Data. Bioinformatics 2015, 31, 572–580. [CrossRef]
3. Menon, R.; Garg, G.; Gasser, R.B.; Ranganathan, S. TranSeqAnnotator: Large-Scale Analysis of Transcriptomic Data. BMC
Bioinform. 2012, 13 (Suppl. 17), S24. [CrossRef]
4. Jin, H.; Liu, Z. A Benchmark for RNA-Seq Deconvolution Analysis under Dynamic Testing Environments. Genome Biol. 2021, 22,
102. [CrossRef]
5. Medina, I.; Carbonell, J.; Pulido, L.; Madeira, S.C.; Goetz, S.; Conesa, A.; Tárraga, J.; Pascual-Montano, A.; Nogales-Cadenas, R.;
Santoyo, J.; et al. Babelomics: An Integrative Platform for the Analysis of Transcriptomics, Proteomics and Genomic Data with
Advanced Functional Profiling. Nucleic Acids Res. 2010, 38, W210–W213. [CrossRef]
6. Matikas, A.; Zerdes, I.; Lövrot, J.; Richard, F.; Sotiriou, C.; Bergh, J.; Valachis, A.; Foukakis, T. Prognostic Implications of
PD-L1 Expression in Breast Cancer: Systematic Review and Meta-Analysis of Immunohistochemistry and Pooled Analysis of
Transcriptomic Data. Clin. Cancer Res. 2019, 25, 5717–5726. [CrossRef]
7. Haas Bueno, R.; Recamonde-Mendoza, M. Meta-Analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved
with Atrial Fibrillation. Mol. Diagn. Ther. 2020, 24, 737–751. [CrossRef] [PubMed]
8. Aevermann, B.D.; Pickett, B.E.; Kumar, S.; Klem, E.B.; Agnihothram, S.; Askovich, P.S.; Bankhead, A.; Bolles, M.; Carter, V.; Chang,
J.; et al. A Comprehensive Collection of Systems Biology Data Characterizing the Host Response to Viral Infection. Sci. Data 2014,
1, 140033. [CrossRef] [PubMed]
9. Kori, M.; Yalcin Arga, K. Potential Biomarkers and Therapeutic Targets in Cervical Cancer: Insights from the Meta-Analysis of
Transcriptomics Data within Network Biomedicine Perspective. PLoS ONE 2018, 13, e0200717. [CrossRef] [PubMed]
10. Patel, H.; Dobson, R.J.B.; Newhouse, S.J. A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data. J. Alzheimers Dis.
2019, 68, 1635–1656. [CrossRef] [PubMed]
11. Zhang, L.-L.; Zhang, Z.-N.; Wu, X.; Jiang, Y.-J.; Fu, Y.-J.; Shang, H. Transcriptomic Meta-Analysis Identifies Gene Expression
Characteristics in Various Samples of HIV-Infected Patients with Nonprogressive Disease. J. Transl. Med. 2017, 15, 191. [CrossRef]
[PubMed]
12. Wilkinson, M.D.; Dumontier, M.; Aalbersberg, I.J.J.; Appleton, G.; Axton, M.; Baak, A.; Blomberg, N.; Boiten, J.-W.; da Silva
Santos, L.B.; Bourne, P.E.; et al. The FAIR Guiding Principles for Scientific Data Management and Stewardship. Sci. Data 2016, 3,
160018. [CrossRef]
13. Taylor, C.F.; Field, D.; Sansone, S.-A.; Aerts, J.; Apweiler, R.; Ashburner, M.; Ball, C.A.; Binz, P.-A.; Bogue, M.; Booth, T.; et al.
Promoting Coherent Minimum Reporting Guidelines for Biological and Biomedical Investigations: The MIBBI Project. Nat.
Biotechnol. 2008, 26, 889–896. [CrossRef] [PubMed]
14. Nicolson, G.L.; Settineri, R.; Ellithorpe, R. Glycophospholipid Formulation with NADH and CoQ10 Significantly Reduces
Intractable Fatigue in Western Blot-Positive ‘Chronic Lyme Disease’ Patients: Preliminary Report. Funct. Foods Health Dis. 2012, 2,
35–47. [CrossRef]
15. Czirjak, L.; Varju, C. Clinical Features of Scleroderma-Like Disorders: A Challenge for the Rheumatologist. Curr. Rheumatol. Rev.
2006, 2, 369–379. [CrossRef]
16. Finsterer, J.; Löscher, W.N.; Wanschitz, J.; Iglseder, S. Orphan Peripheral Neuropathies. J. Neuromuscul. Dis. 2021, 8, 1–23.
[CrossRef] [PubMed]
17. González-Sanz, R.; Mata, M.; Bermejo-Martín, J.; Álvarez, A.; Cortijo, J.; Melero, J.A.; Martínez, I. ISG15 Is Upregulated in
Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation. J. Virol. 2016, 90, 3428–3438.
[CrossRef]
18. Drori, Y.; Jacob-Hirsch, J.; Pando, R.; Glatman-Freedman, A.; Friedman, N.; Mendelson, E.; Mandelboim, M. Influenza A Virus
Inhibits RSV Infection via a Two-Wave Expression of IFIT Proteins. Viruses 2020, 12, 1171. [CrossRef]
19. Zhang, Y.; Mao, D.; Roswit, W.T.; Jin, X.; Patel, A.C.; Patel, D.A.; Agapov, E.; Wang, Z.; Tidwell, R.M.; Atkinson, J.J.; et al.
PARP9-DTX3L Ubiquitin Ligase Targets Host Histone H2BJ and Viral 3C Protease to Enhance Interferon Signaling and Control
Viral Infection. Nat. Immunol. 2015, 16, 1215–1227. [CrossRef]
20. Ruiduo, C.; Ying, D.; Qiwei, W. CXCL9 Promotes the Progression of Diffuse Large B-Cell Lymphoma through up-Regulating
β-Catenin. Biomed. Pharmacother. 2018, 107, 689–695. [CrossRef]
21. Shah, N.; Cabanillas, F.; McIntyre, B.; Feng, L.; McLaughlin, P.; Rodriguez, M.A.; Romaguera, J.; Younes, A.; Hagemeister, F.B.;
Kwak, L.; et al. Prognostic Value of Serum CD44, Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1
Levels in Patients with Indolent Non-Hodgkin Lymphomas. Leuk. Lymphoma 2012, 53, 50–56. [CrossRef]
22. Pullarkat, V.A.; Lacayo, N.J.; Jabbour, E.; Rubnitz, J.E.; Bajel, A.; Laetsch, T.W.; Leonard, J.; Colace, S.I.; Khaw, S.L.; Fleming,
S.A.; et al. Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute
Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancer Discov. 2021, 11, 1440–1453. [CrossRef]
23. Faramand, R.; Jain, M.; Staedtke, V.; Kotani, H.; Bai, R.; Reid, K.; Lee, S.B.; Spitler, K.; Wang, X.; Cao, B.; et al. Tumor
Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell
Lymphoma Treated with Axicabtagene Ciloleucel. Clin. Cancer Res. 2020, 26, 4823–4831. [CrossRef]
Data 2021, 6, 75 9 of 10

24. Li, M.; Chiang, Y.-L.; Lyssiotis, C.A.; Teater, M.R.; Hong, J.Y.; Shen, H.; Wang, L.; Hu, J.; Jing, H.; Chen, Z.; et al. Non-Oncogene
Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer Cell 2019, 35, 916–931.e9. [CrossRef] [PubMed]
25. Porpaczy, E.; Tripolt, S.; Hoelbl-Kovacic, A.; Gisslinger, B.; Bago-Horvath, Z.; Casanova-Hevia, E.; Clappier, E.; Decker, T.;
Fajmann, S.; Fux, D.A.; et al. Aggressive B-Cell Lymphomas in Patients with Myelofibrosis Receiving JAK1/2 Inhibitor Therapy.
Blood 2018, 132, 694–706. [CrossRef]
26. Teater, M.; Dominguez, P.M.; Redmond, D.; Chen, Z.; Ennishi, D.; Scott, D.W.; Cimmino, L.; Ghione, P.; Chaudhuri, J.; Gascoyne,
R.D.; et al. AICDA Drives Epigenetic Heterogeneity and Accelerates Germinal Center-Derived Lymphomagenesis. Nat. Commun.
2018, 9, 222. [CrossRef]
27. Raju, S.; Kretzmer, L.Z.; Koues, O.I.; Payton, J.E.; Oltz, E.M.; Cashen, A.; Polic, B.; Schreiber, R.D.; Shaw, A.S.; Markiewicz,
M.A. NKG2D-NKG2D Ligand Interaction Inhibits the outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo. J.
Immunol. 2016, 196, 4805–4813. [CrossRef] [PubMed]
28. Rouhigharabaei, L.; Finalet Ferreiro, J.; Tousseyn, T.; van der Krogt, J.-A.; Put, N.; Haralambieva, E.; Graux, C.; Maes, B.; Vicente,
C.; Vandenberghe, P.; et al. Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated
Isoforms of FOXP1. PLoS ONE 2014, 9, e85851. [CrossRef]
29. Verma, A.; Jiang, Y.; Du, W.; Fairchild, L.; Melnick, A.; Elemento, O. Transcriptome Sequencing Reveals Thousands of Novel Long
Non-Coding RNAs in B Cell Lymphoma. Genome Med. 2015, 7, 110. [CrossRef] [PubMed]
30. Bouquet, J.; Soloski, M.J.; Swei, A.; Cheadle, C.; Federman, S.; Billaud, J.-N.; Rebman, A.W.; Kabre, B.; Halpert, R.; Boorgula, M.;
et al. Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for
Acute Lyme Disease. MBio 2016, 7, e00100–e00116. [CrossRef]
31. Jeong, I.; Lim, J.-H.; Oh, D.K.; Kim, W.J.; Oh, Y.-M. Gene Expression Profile of Human Lung in a Relatively Early Stage of COPD
with Emphysema. Int. J. Chronic Obstr. Pulm. Dis. 2018, 13, 2643–2655. [CrossRef]
32. Li, M.; Zhao, L.-M.; Li, S.-L.; Li, J.; Gao, B.; Wang, F.-F.; Wang, S.-P.; Hu, X.-H.; Cao, J.; Wang, G.-Y. Differentially Expressed
LncRNAs and MRNAs Identified by NGS Analysis in Colorectal Cancer Patients. Cancer Med. 2018, 7, 4650–4664. [CrossRef]
33. Deng, X.; Li, S.; Kong, F.; Ruan, H.; Xu, X.; Zhang, X.; Wu, Z.; Zhang, L.; Xu, Y.; Yuan, H.; et al. Long Noncoding RNA PiHL
Regulates P53 Protein Stability through GRWD1/RPL11/MDM2 Axis in Colorectal Cancer. Theranostics 2020, 10, 265–280.
[CrossRef] [PubMed]
34. Lazar, S.B.; Pongor, L.; Li, X.L.; Grammatikakis, I.; Muys, B.R.; Dangelmaier, E.A.; Redon, C.E.; Jang, S.-M.; Walker, R.L.; Tang, W.;
et al. Genome-Wide Analysis of the FOXA1 Transcriptional Network Identifies Novel Protein-Coding and Long Noncoding RNA
Targets in Colorectal Cancer Cells. Mol. Cell. Biol. 2020, 40. [CrossRef] [PubMed]
35. Lu, S.; Zhu, N.; Guo, W.; Wang, X.; Li, K.; Yan, J.; Jiang, C.; Han, S.; Xiang, H.; Wu, X.; et al. RNA-Seq Revealed a Circular
RNA-MicroRNA-MRNA Regulatory Network in Hantaan Virus Infection. Front. Cell. Infect. Microbiol. 2020, 10, 97. [CrossRef]
[PubMed]
36. Li, Y.; Quan, C.; Xing, W.; Wang, P.; Gao, J.; Zhang, Z.; Jiang, X.; Ma, C.; Carr, M.J.; He, Q.; et al. Rapid Humoral Immune
Responses Are Required for Recovery from Haemorrhagic Fever with Renal Syndrome Patients. Emerg. Microbes Infect. 2020, 9,
2303–2314. [CrossRef] [PubMed]
37. Blanco-Melo, D.; Nilsson-Payant, B.E.; Liu, W.-C.; Uhl, S.; Hoagland, D.; Møller, R.; Jordan, T.X.; Oishi, K.; Panis, M.; Sachs, D.;
et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 2020, 181, 1036–1045.e9. [CrossRef]
[PubMed]
38. Jenks, S.A.; Cashman, K.S.; Zumaquero, E.; Marigorta, U.M.; Patel, A.V.; Wang, X.; Tomar, D.; Woodruff, M.C.; Simon, Z.;
Bugrovsky, R.; et al. Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in
Systemic Lupus Erythematosus. Immunity 2018, 49, 725–739.e6. [CrossRef]
39. Scharer, C.D.; Blalock, E.L.; Mi, T.; Barwick, B.G.; Jenks, S.A.; Deguchi, T.; Cashman, K.S.; Neary, B.E.; Patterson, D.G.; Hicks, S.L.;
et al. Epigenetic Programming Underpins B Cell Dysfunction in Human SLE. Nat. Immunol. 2019, 20, 1071–1082. [CrossRef]
40. Wang, S.; Wang, J.; Kumar, V.; Karnell, J.L.; Naiman, B.; Gross, P.S.; Rahman, S.; Zerrouki, K.; Hanna, R.; Morehouse, C.; et al.
IL-21 Drives Expansion and Plasma Cell Differentiation of Autoreactive CD11chiT-Bet+ B Cells in SLE. Nat. Commun. 2018, 9,
1758. [CrossRef]
41. Zhang, X.; Chu, H.; Wen, L.; Shuai, H.; Yang, D.; Wang, Y.; Hou, Y.; Zhu, Z.; Yuan, S.; Yin, F.; et al. Competing Endogenous RNA
Network Profiling Reveals Novel Host Dependency Factors Required for MERS-CoV Propagation. Emerg. Microbes Infect. 2020, 9,
733–746. [CrossRef]
42. Yuan, S.; Chu, H.; Chan, J.F.-W.; Ye, Z.-W.; Wen, L.; Yan, B.; Lai, P.-M.; Tee, K.-M.; Huang, J.; Chen, D.; et al. SREBP-Dependent
Lipidomic Reprogramming as a Broad-Spectrum Antiviral Target. Nat. Commun. 2019, 10, 120. [CrossRef]
43. Aprianto, R.; Slager, J.; Holsappel, S.; Veening, J.-W. Time-Resolved Dual RNA-Seq Reveals Extensive Rewiring of Lung Epithelial
and Pneumococcal Transcriptomes during Early Infection. Genome Biol. 2016, 17, 198. [CrossRef] [PubMed]
44. Kuipers, K.; Lokken, K.L.; Zangari, T.; Boyer, M.A.; Shin, S.; Weiser, J.N. Age-Related Differences in IL-1 Signaling and Capsule
Serotype Affect Persistence of Streptococcus Pneumoniae Colonization. PLoS Pathog. 2018, 14, e1007396. [CrossRef]
45. Jochems, S.P.; Marcon, F.; Carniel, B.F.; Holloway, M.; Mitsi, E.; Smith, E.; Gritzfeld, J.F.; Solórzano, C.; Reiné, J.; Pojar, S.; et al.
Inflammation Induced by Influenza Virus Impairs Human Innate Immune Control of Pneumococcus. Nat. Immunol. 2018, 19,
1299–1308. [CrossRef] [PubMed]
Data 2021, 6, 75 10 of 10

46. Weight, C.M.; Venturini, C.; Pojar, S.; Jochems, S.P.; Reiné, J.; Nikolaou, E.; Solórzano, C.; Noursadeghi, M.; Brown, J.S.; Ferreira,
D.M.; et al. Microinvasion by Streptococcus Pneumoniae Induces Epithelial Innate Immunity during Colonisation at the Human
Mucosal Surface. Nat. Commun. 2019, 10, 3060. [CrossRef] [PubMed]
47. Lamers, M.M.; Beumer, J.; van der Vaart, J.; Knoops, K.; Puschhof, J.; Breugem, T.I.; Ravelli, R.B.G.; Paul van Schayck, J.; Mykytyn,
A.Z.; Duimel, H.Q.; et al. SARS-CoV-2 Productively Infects Human Gut Enterocytes. Science 2020, 369, 50–54. [CrossRef]
48. Duan, F.; Guo, L.; Yang, L.; Han, Y.; Thakur, A.; Nilsson-Payant, B.E.; Wang, P.; Zhang, Z.; Ma, C.Y.; Zhou, X.; et al. Modeling
COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-Inflammatory Macrophages with
ACE2 Inhibition Against SARS-CoV-2. Res. Sq. 2020. [CrossRef]
49. Vanderheiden, A.; Ralfs, P.; Chirkova, T.; Upadhyay, A.A.; Zimmerman, M.G.; Bedoya, S.; Aoued, H.; Tharp, G.M.; Pellegrini,
K.L.; Manfredi, C.; et al. Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures. J.
Virol. 2020, 94. [CrossRef] [PubMed]
50. Orjuela, S.; Huang, R.; Hembach, K.M.; Robinson, M.D.; Soneson, C. ARMOR: An Automated Reproducible MOdular Workflow
for Preprocessing and Differential Analysis of RNA-Seq Data. G3 Genes Genomes Genet. 2019, 9, 2089–2096. [CrossRef] [PubMed]
51. Köster, J.; Rahmann, S. Snakemake—A Scalable Bioinformatics Workflow Engine. Bioinformatics 2012, 28, 2520–2522. [CrossRef]
[PubMed]
52. Babraham Bioinformatics—Trim Galore! Available online: https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/
(accessed on 7 June 2021).
53. Babraham Bioinformatics—FastQC A Quality Control Tool for High Throughput Sequence Data. Available online: https:
//www.bioinformatics.babraham.ac.uk/projects/fastqc/ (accessed on 7 June 2021).
54. Patro, R.; Duggal, G.; Love, M.I.; Irizarry, R.A.; Kingsford, C. Salmon Provides Fast and Bias-Aware Quantification of Transcript
Expression. Nat. Methods 2017, 14, 417–419. [CrossRef] [PubMed]
55. Robinson, M.D.; McCarthy, D.J.; Smyth, G.K. EdgeR: A Bioconductor Package for Differential Expression Analysis of Digital
Gene Expression Data. Bioinformatics 2010, 26, 139–140. [CrossRef] [PubMed]
56. Wu, D.; Smyth, G.K. Camera: A Competitive Gene Set Test Accounting for Inter-Gene Correlation. Nucleic Acids Res. 2012, 40,
e133. [CrossRef]
57. Nowicka, M.; Robinson, M.D. DRIMSeq: A Dirichlet-Multinomial Framework for Multivariate Count Outcomes in Genomics.
F1000Research 2016, 5, 1356. [CrossRef] [PubMed]
58. Tarca, A.L.; Draghici, S.; Khatri, P.; Hassan, S.S.; Mittal, P.; Kim, J.-S.; Kim, C.J.; Kusanovic, J.P.; Romero, R. A Novel Signaling
Pathway Impact Analysis. Bioinformatics 2009, 25, 75–82. [CrossRef]