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Article ; Online: VExD: a curated resource for human gene expression alterations following viral infection.

Dexheimer, Phillip J / Pujato, Mario / Roskin, Krishna M / Weirauch, Matthew T

2023 Volume 13, Issue 10

Abstract: Much of the host antiviral response is mediated through changes to host gene expression levels. Likewise, viruses induce changes to host gene expression levels in order to promote the viral life cycle and evade the host immune system. However, there is ... ...

Abstract	Much of the host antiviral response is mediated through changes to host gene expression levels. Likewise, viruses induce changes to host gene expression levels in order to promote the viral life cycle and evade the host immune system. However, there is no resource that specifically collects human gene expression levels pre- and post-virus infection. Further, public gene expression repositories do not contain enough specialized metadata to easily find relevant experiments. Here, we present the Virus Expression Database (VExD), a freely available website and database, that collects human gene expression datasets in response to viral infection. VExD contains ∼8,000 uniformly processed samples obtained from 289 studies examining 51 distinct human viruses. We show that the VExD processing pipeline captures known antiviral responses in the form of interferon-stimulated genes. We further show that the datasets collected in VExD can be used to quickly identify supporting data for experiments performed in human cells or model organisms. VExD is freely available at https://vexd.cchmc.org/.
MeSH term(s)	Humans ; Gene Expression Regulation ; Antiviral Agents/pharmacology ; Virus Diseases/genetics ; Viruses/genetics ; Gene Expression
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2023-08-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkad176
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Deciphering cis-regulatory grammar with deep learning.

Miraldi, Emily R / Chen, Xiaoting / Weirauch, Matthew T

Nature genetics

2021 Volume 53, Issue 3, Page(s) 266–268

MeSH term(s)	Deep Learning ; Linguistics
Language	English
Publishing date	2021-03-08
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-021-00814-1
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Article ; Online: Runx Transcription Factors in T Cells-What Is Beyond Thymic Development?

Korinfskaya, Svetlana / Parameswaran, Sreeja / Weirauch, Matthew T / Barski, Artem

Frontiers in immunology

2021 Volume 12, Page(s) 701924

Abstract: Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood ... ...

Abstract	Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood cell development during different stages of cell lineage specification. However, recent studies show evidence of complex relationships between RUNX proteins, chromatin-modifying machinery, the cytoskeleton and different transcription factors in various non-embryonic contexts, including mature T cell homeostasis, inflammation and cancer. In this review, we discuss the diversity of Runx functions in mature T helper cells, such as production of cytokines and chemokines by different CD4 T cell populations; apoptosis; and immunologic memory acquisition. We then briefly cover recent findings about the contribution of
MeSH term(s)	Animals ; Core Binding Factor alpha Subunits/immunology ; Humans ; Immunity/immunology ; Immunologic Memory/immunology ; Inflammation/immunology ; T-Lymphocytes/immunology ; Thymus Gland/immunology
Chemical Substances	Core Binding Factor alpha Subunits
Language	English
Publishing date	2021-08-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.701924
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Article ; Online: Frontotemporal degeneration genetic risk loci and transcription regulation as a possible mechanistic link to disease risk.

Sawyer, Russell P / Stone, Hillarey K / Salim, Hanan / Lu, Xiaoming / Weirauch, Matthew T / Kottyan, Leah

Medicine

2022 Volume 101, Issue 41, Page(s) e31078

Abstract: The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and ... ...

Abstract	The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and nominate specific transcriptional regulators as potential key players in the etiology of this disease. A list of GVs associated with FTD was compiled from published GWAS. The regulatory element locus intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk GVs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation (ChIP-seq) experiments. After linkage disequilibrium expansion of the previously reported tag associated GVs, we identified 914 GV at 47 independent risk loci. Using the RELI algorithm, we identified several transcriptional regulators with enriched binding at FTD risk loci (0.05 < corrected P value <1.18 × 10-27), including Tripartite motif-containing 28 (TRIM28) and Chromodomain-Helicase DNA-binding 1 (CHD1) which have previously observed roles in FTD. FTD is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established FTD risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response as important in the genetic etiology of FTD.
MeSH term(s)	Atrophy ; DNA ; Frontotemporal Dementia/genetics ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors ; DNA (9007-49-2)
Language	English
Publishing date	2022-09-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000031078
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Article ; Online: Gene-environment interactions and their impact on human health.

Virolainen, Samuel J / VonHandorf, Andrew / Viel, Kenyatta C M F / Weirauch, Matthew T / Kottyan, Leah C

Genes and immunity

2022 Volume 24, Issue 1, Page(s) 1–11

Abstract: The molecular processes underlying human health and disease are highly complex. Often, genetic and environmental factors contribute to a given disease or phenotype in a non-additive manner, yielding a gene-environment (G × E) interaction. In this work, ... ...

Abstract	The molecular processes underlying human health and disease are highly complex. Often, genetic and environmental factors contribute to a given disease or phenotype in a non-additive manner, yielding a gene-environment (G × E) interaction. In this work, we broadly review current knowledge on the impact of gene-environment interactions on human health. We first explain the independent impact of genetic variation and the environment. We next detail well-established G × E interactions that impact human health involving environmental toxicants, pollution, viruses, and sex chromosome composition. We conclude with possibilities and challenges for studying G × E interactions.
MeSH term(s)	Humans ; Gene-Environment Interaction ; Phenotype
Language	English
Publishing date	2022-12-30
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2060566-3
ISSN	1476-5470 ; 1466-4879
ISSN (online)	1476-5470
ISSN	1466-4879
DOI	10.1038/s41435-022-00192-6
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Article: After the Infection: A Survey of Pathogens and Non-communicable Human Disease.

Lape, Michael / Schnell, Daniel / Parameswaran, Sreeja / Ernst, Kevin / Salomonis, Nathan / Martin, Lisa J / Harnett, Brett M / Kottyan, Leah C / Weirauch, Matthew T

medRxiv : the preprint server for health sciences

2023

Abstract: There are many well-established relationships between pathogens and human disease, but far fewer when focusing on non-communicable diseases (NCDs). We leverage data from The UK Biobank and TriNetX to perform a systematic survey across 20 pathogens and ... ...

Abstract	There are many well-established relationships between pathogens and human disease, but far fewer when focusing on non-communicable diseases (NCDs). We leverage data from The UK Biobank and TriNetX to perform a systematic survey across 20 pathogens and 426 diseases, focused primarily on NCDs. To this end, we assess the association between disease status and infection history proxies. We identify 206 pathogen-disease pairs that replicate in both cohorts. We replicate many established relationships, including
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.14.23295428
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Article: TET1 regulates responses to house dust mite by altering chromatin accessibility, DNA methylation, and gene expression in airway epithelial cells.

Brown, Anthony P / Parameswaran, Sreeja / Cai, Lucy / Elston, Sweeney / Pham, Chi / Barski, Artem / Weirauch, Matthew T / Ji, Hong

Research square

2023

Abstract: Background: Previous studies have identified TET1 as a potential key regulator of genes linked to asthma. TET1 has been shown to transcriptionally respond to house dust mite extract, an allergen known to directly cause allergic asthma development, and ... ...

Abstract	Background: Previous studies have identified TET1 as a potential key regulator of genes linked to asthma. TET1 has been shown to transcriptionally respond to house dust mite extract, an allergen known to directly cause allergic asthma development, and regulate the expression of genes involved in asthma. How TET1 regulates expression of these genes, however, is unknown. TET1 is a DNA demethylase; therefore, most prior research on TET1-based gene regulation has focused on how TET1 affects methylation. However, TET1 can also interact directly with transcription factors and histone modifiers to regulate gene expression. Understanding how TET1 regulates expression to contribute to allergic responses and asthma development thus requires a comprehensive approach. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility and histone modifications in control and TET1 knockdown human bronchial epithelial cells treated or untreated with house dust mite extract. Results: Throughout our analyses, we detected strong similarities between the effects of Conclusions: TET1 regulates gene expression through different mechanisms (DNA methylation and chromatin accessibility) in different parts of the genome in the airway epithelial cells, which mediates inflammatory responses to allergen. Collectively, our data suggest novel molecular mechanisms through which TET1 regulates critical pathways following allergen challenges and contributes to the development of asthma.
Language	English
Publishing date	2023-12-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3726852/v1
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Article ; Online: NOMe-HiC: joint profiling of genetic variant, DNA methylation, chromatin accessibility, and 3D genome in the same DNA molecule.

Fu, Hailu / Zheng, Haizi / Chen, Xiaoting / Weirauch, Matthew T / Muglia, Louis J / Wang, Li / Liu, Yaping

Genome biology

2023 Volume 24, Issue 1, Page(s) 50

Abstract: Cis-regulatory elements are coordinated to regulate the expression of their targeted genes. However, the joint measurement of cis-regulatory elements' activities and their interactions in spatial proximity is limited by the current sequencing approaches. ...

Abstract	Cis-regulatory elements are coordinated to regulate the expression of their targeted genes. However, the joint measurement of cis-regulatory elements' activities and their interactions in spatial proximity is limited by the current sequencing approaches. We describe a method, NOMe-HiC, which simultaneously captures single-nucleotide polymorphisms, DNA methylation, chromatin accessibility (GpC methyltransferase footprints), and chromosome conformation changes from the same DNA molecule, together with the transcriptome, in a single assay. NOMe-HiC shows high concordance with state-of-the-art mono-omic assays across different molecular measurements and reveals coordinated chromatin accessibility at distal genomic segments in spatial proximity and novel types of long-range allele-specific chromatin accessibility.
MeSH term(s)	Chromatin/genetics ; DNA Methylation ; Nucleosomes ; Genome ; DNA/metabolism
Chemical Substances	Chromatin ; Nucleosomes ; DNA (9007-49-2)
Language	English
Publishing date	2023-03-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-023-02889-x
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Article ; Online: Prediction of cooperative homeodomain DNA binding sites from high-throughput-SELEX data.

Cain, Brittany / Webb, Jordan / Yuan, Zhenyu / Cheung, David / Lim, Hee-Woong / Kovall, Rhett A / Weirauch, Matthew T / Gebelein, Brian

Nucleic acids research

2023 Volume 51, Issue 12, Page(s) 6055–6072

Abstract: Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many developmental processes. Yet, biochemical data reveal that most bind highly similar ... ...

Abstract	Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many developmental processes. Yet, biochemical data reveal that most bind highly similar DNA sequences. Defining how homeodomain proteins achieve DNA binding specificity has therefore been a long-standing goal. Here, we developed a novel computational approach to predict cooperative dimeric binding of homeodomain proteins using High-Throughput (HT) SELEX data. Importantly, we found that 15 of 88 homeodomain factors form cooperative homodimer complexes on DNA sites with precise spacing requirements. Approximately one third of the paired-like homeodomain proteins cooperatively bind palindromic sequences spaced 3 bp apart, whereas other homeodomain proteins cooperatively bind sites with distinct orientation and spacing requirements. Combining structural models of a paired-like factor with our cooperativity predictions identified key amino acid differences that help differentiate between cooperative and non-cooperative factors. Finally, we confirmed predicted cooperative dimer sites in vivo using available genomic data for a subset of factors. These findings demonstrate how HT-SELEX data can be computationally mined to predict cooperativity. In addition, the binding site spacing requirements of select homeodomain proteins provide a mechanism by which seemingly similar AT-rich DNA sequences can preferentially recruit specific homeodomain factors.
MeSH term(s)	Animals ; Binding Sites ; DNA/chemistry ; Homeodomain Proteins/metabolism ; High-Throughput Nucleotide Sequencing
Chemical Substances	DNA (9007-49-2) ; Homeodomain Proteins
Language	English
Publishing date	2023-03-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad318
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Article: Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations.

Sun, Chengyi / Swoboda, Casey O / Petrany, Michael J / Parameswaran, Sreeja / VonHandorf, Andrew / Weirauch, Matthew T / Lepper, Christoph / Millay, Douglas P

bioRxiv : the preprint server for biology

2023

Abstract: Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal ... ...

Abstract	Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in syncytial cells that already harbor hundreds of nuclei. To begin to answer this long-standing question, we utilized nuclear RNA-sequencing approaches and developed a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.24.554609
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