Conserved and species-specific transcription factor co-binding patterns drive divergent gene regulation in human and mouse

Adam G Diehl; Alan P Boyle

doi:10.1093/nar/gky018

Cistrome-GO: a web server for functional enrichment analysis of transcription factor ChIP-seq peaks

Nucleic Acids Research ◽

10.1093/nar/gkz332 ◽

2019 ◽

Vol 47 (W1) ◽

pp. W206-W211 ◽

Cited By ~ 15

Author(s):

Shaojuan Li ◽

Changxin Wan ◽

Rongbin Zheng ◽

Jingyu Fan ◽

Xin Dong ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transcription Factor ◽

Target Genes ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Differential Gene ◽

Direct Target ◽

Human And Mouse

AbstractCharacterizing the ontologies of genes directly regulated by a transcription factor (TF), can help to elucidate the TF’s biological role. Previously, we developed a widely used method, BETA, to integrate TF ChIP-seq peaks with differential gene expression (DGE) data to infer direct target genes. Here, we provide Cistrome-GO, a website implementation of this method with enhanced features to conduct ontology analyses of gene regulation by TFs in human and mouse. Cistrome-GO has two working modes: solo mode for ChIP-seq peak analysis; and ensemble mode, which integrates ChIP-seq peaks with DGE data. Cistrome-GO is freely available at http://go.cistrome.org/.

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Comparative Transcriptomics Analyses in Livers of Mice, Humans, and Humanized Mice Define Human-Specific Gene Networks

Cells ◽

10.3390/cells9122566 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2566

Author(s):

Chengfei Jiang ◽

Ping Li ◽

Xiangbo Ruan ◽

Yonghe Ma ◽

Kenji Kawai ◽

...

Keyword(s):

Gene Regulation ◽

Gene Networks ◽

Liver Cells ◽

Biological Processes ◽

Divergent Gene ◽

Specific Regulation ◽

The Impact ◽

Gene Regulations ◽

Human And Mouse ◽

Human Specific

Mouse is the most widely used animal model in biomedical research, but it remains unknown what causes the large number of differentially regulated genes between human and mouse livers identified in recent years. In this report, we aim to determine whether these divergent gene regulations are primarily caused by environmental factors or some of them are the result of cell-autonomous differences in gene regulation in human and mouse liver cells. The latter scenario would suggest that many human genes are subject to human-specific regulation and can only be adequately studied in a human or humanized system. To understand the similarity and divergence of gene regulation between human and mouse livers, we performed stepwise comparative analyses in human, mouse, and humanized livers with increased stringency to gradually remove the impact of factors external to liver cells, and used bioinformatics approaches to retrieve gene networks to ascertain the regulated biological processes. We first compared liver gene regulation by fatty liver disease in human and mouse under the condition where the impact of genetic and gender biases was minimized, and identified over 50% of all commonly regulated genes, that exhibit opposite regulation by fatty liver disease in human and mouse. We subsequently performed more stringent comparisons when a single specific transcriptional or post-transcriptional event was modulated in vitro or vivo or in liver-specific humanized mice in which human and mouse hepatocytes colocalize and share a common circulation. Intriguingly and strikingly, the pattern of a high percentage of oppositely regulated genes persists under well-matched conditions, even in the liver of the humanized mouse model, which represents the most closely matched in vivo condition for human and mouse liver cells that is experimentally achievable. Gene network analyses further corroborated the results of oppositely regulated genes and revealed substantial differences in regulated biological processes in human and mouse cells. We also identified a list of regulated lncRNAs that exhibit very limited conservation and could contribute to these differential gene regulations. Our data support that cell-autonomous differences in gene regulation might contribute substantially to the divergent gene regulation between human and mouse livers and there are a significant number of biological processes that are subject to human-specific regulation and need to be carefully considered in the process of mouse to human translation.

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RNA Polymerase I Transcription in a Brassica Interspecific Hybrid and Its Progenitors: Tests of Transcription Factor Involvement in Nucleolar Dominance

Genetics ◽

10.1093/genetics/152.1.451 ◽

1999 ◽

Vol 152 (1) ◽

pp. 451-460

Author(s):

Matthew Frieman ◽

Z Jeffrey Chen ◽

Julio Saez-Vasquez ◽

L Annie Shen ◽

Craig S Pikaard

Keyword(s):

Transcription Factor ◽

Cytosine Methylation ◽

Transcription Factor Binding ◽

The Other ◽

Rrna Genes ◽

Nucleolar Dominance ◽

Specific Transcription Factor ◽

Factor Binding ◽

Species Specific

Abstract In interspecific hybrids or allopolyploids, often one parental set of ribosomal RNA genes is transcribed and the other is silent, an epigenetic phenomenon known as nucleolar dominance. Silencing is enforced by cytosine methylation and histone deacetylation, but the initial discrimination mechanism is unknown. One hypothesis is that a species-specific transcription factor is inactivated, thereby silencing one set of rRNA genes. Another is that dominant rRNA genes have higher binding affinities for limiting transcription factors. A third suggests that selective methylation of underdominant rRNA genes blocks transcription factor binding. We tested these hypotheses using Brassica napus (canola), an allotetraploid derived from B. rapa and B. oleracea in which only B. rapa rRNA genes are transcribed. B. oleracea and B. rapa rRNA genes were active when transfected into protoplasts of the other species, which argues against the species-specific transcription factor model. B. oleracea and B. rapa rRNA genes also competed equally for the pol I transcription machinery in vitro and in vivo. Cytosine methylation had no effect on rRNA gene transcription in vitro, which suggests that transcription factor binding was unimpaired. These data are inconsistent with the prevailing models and point to discrimination mechanisms that are likely to act at a chromosomal level.

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Transcription factor co-binding patterns drive conserved regulatory outcomes

10.1101/189571 ◽

2017 ◽

Author(s):

Adam G. Diehl ◽

Alan P. Boyle

Keyword(s):

Transcription Factor ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Regulatory Control ◽

Regulatory Sequence ◽

Transcriptional Regulatory ◽

Genetic Mechanisms ◽

Transcriptional Regulatory Mechanisms ◽

Species Specific ◽

Human And Mouse

ABSTRACTThe mouse has been widely used as a model system in which to study human genetic mechanisms. However, part of the difficulty in translating findings from mouse is that, despite high levels of gene conservation, regulatory control networks between human and mouse have been extensively rewired. To understand common themes of regulatory control we look beyond physical sharing of regulatory sequence, where extensive turnover of individual transcription factor binding sites complicates cross-species prediction of specific functions, and instead look at conserved properties of the regulatory code itself. We define regulatory conservation in terms of a grammar with shared, species-specific, and tissue-specific segments, and show that this grammar is more predictive of shared chromatin states and gene expression profiles than shared occupancy alone. Furthermore, we demonstrate a marked enrichment of disease associated variation in conserved grammatical patterns. These findings offer new understanding of transcriptional regulatory mechanisms shared between human and mouse.

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