Predicting gene expression in T cell differentiation from histone modifications and transcription factor binding affinities by linear mixture models

The transcription factor Ets1 contributes to the differentiation of CD8 lineage cells in the thymus, but how it does so is not understood. In this study, we demonstrate that Ets1 is required for the proper termination of CD4 expression during the differentiation of major histocompatability class 1 (MHC I)–restricted thymocytes, but not for other events associated with their positive selection, including the initiation of cytotoxic gene expression, corticomedullary migration, or thymus exit. We further show that Ets1 promotes expression of Runx3, a transcription factor important for CD8 T cell differentiation and the cessation of Cd4 gene expression. Enforced Runx3 expression in Ets1-deficient MHC I–restricted thymocytes largely rescued their impaired Cd4 silencing, indicating that Ets1 is not required for Runx3 function. Finally, we document that Ets1 binds at least two evolutionarily conserved regions within the Runx3 gene in vivo, supporting the possibility that Ets1 directly contributes to Runx3 transcription. These findings identify Ets1 as a key player during CD8 lineage differentiation and indicate that it acts, at least in part, by promoting Runx3 expression.

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Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels

10.1101/006171 ◽

2014 ◽

Cited By ~ 1

Author(s):

Nicholas E. Banovich ◽

Xun Lan ◽

Graham McVicker ◽

Bryce van de Geijn ◽

Jacob F. Degner ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transcription Factor ◽

Genetic Variation ◽

Histone Modifications ◽

Transcription Factor Binding ◽

Dnase I ◽

Expression Levels ◽

Factor Binding ◽

Quantitative Changes

AbstractDNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)—i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.Author SummaryDNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.

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Regulation of human papillomavirus type 31 gene expression during the differentiation-dependent life cycle through histone modifications and transcription factor binding

Virology ◽

10.1016/j.virol.2007.12.011 ◽

2008 ◽

Vol 374 (2) ◽

pp. 371-380 ◽

Cited By ~ 41

Author(s):

Tonia R. Wooldridge ◽

Laimonis A. Laimins

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Human Papillomavirus ◽

Life Cycle ◽

Histone Modifications ◽

Transcription Factor Binding ◽

Factor Binding

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Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction

Nucleic Acids Research ◽

10.1093/nar/gkw1061 ◽

2016 ◽

Vol 45 (1) ◽

pp. 54-66 ◽

Cited By ~ 54

Author(s):

Florian Schmidt ◽

Nina Gasparoni ◽

Gilles Gasparoni ◽

Kathrin Gianmoena ◽

Cristina Cadenas ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcription Factor Binding ◽

Open Chromatin ◽

Binding Affinities ◽

Factor Binding

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Dynamic reorganization of chromatin structure and selective DNA demethylation prior to stable enhancer complex formation during differentiation of primary hematopoietic cells in vitro

Blood ◽

10.1182/blood-2003-09-3323 ◽

2004 ◽

Vol 103 (8) ◽

pp. 2950-2955 ◽

Cited By ~ 45

Author(s):

Hiromi Tagoh ◽

Svitlana Melnik ◽

Pascal Lefevre ◽

Suyinn Chong ◽

Arthur D. Riggs ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cell Differentiation ◽

Chromatin Structure ◽

Molecular Mechanisms ◽

Transcription Factor Binding ◽

Dna Demethylation ◽

Mouse Bone Marrow ◽

Cell Fate Decisions ◽

Factor Binding

Abstract In order to gain insights in the true molecular mechanisms involved in cell fate decisions, it is important to study the molecular details of gene activation where such decisions occur, which is at the level of the chromatin structure of individual genes. In the study presented here we addressed this issue and examined the dynamic development of an active chromatin structure at the chicken lysozyme locus during the differentiation of primary myeloid cells from transgenic mouse bone marrow. Using in vivo footprinting we found that stable enhancer complex assembly and high-level gene expression are late events in cell differentiation. However, even before the onset of gene expression and stable transcription factor binding, specific chromatin alterations are observed. This includes changes in DNA topology and the selective demethylation of CpG dinucleotides located in the cores of critical transcription factor binding sites, but not in flanking DNA. These results firmly support the idea that epigenetic programs guiding blood cell differentiation are engraved into the chromatin of lineage-specific genes and that such chromatin changes are implemented before cell lineage specification. (Blood. 2004;103:2950-2955)

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