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Lineage-specific transcription factors regulate DNA methylation dynamics during hematopoietic development [Methylation]

ABSTRACT: DNA methylation is a major epigenetic modification for gene silencing and is dramatically altered spatiotemporally during cellular development. However, the roles of DNA methylation dynamics and regulation in cellular development remain unclear. The present analyses of DNA methylome dynamics during hematopoietic development suggest that DNA demethylation pre-defines the gene expression potential of terminal differentiation-specific genes at the progenitor cell stage and is regulated by lineage-specific transcription factors (TFs). Demethylation of majority of hypo-methylated CpGs in terminally differentiated cells occurs during the progenitor cell stage and is associated with rapid upregulation of terminal differentiation-specific genes. Accordingly, TF overrepresentation analyses indicated that lineage-specific TFs regulate DNA demethylation. The present experiments show that RUNX1 induces site-directed active DNA demethylation by recruiting DNA demethylation enzymes. Collectively, the present data indicate an integrated system of DNA methylation and gene expression during cellular development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85523 | GEO | 2017/08/10

SECONDARY ACCESSION(S): PRJNA338748

REPOSITORIES: GEO

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Lineage-specific transcription factors regulate DNA methylation dynamics during hematopoietic development [ChIP-Seq]

Project description:DNA methylation is a major epigenetic modification for gene silencing and is dramatically altered spatiotemporally during cellular development. However, the roles of DNA methylation dynamics and regulation in cellular development remain unclear. The present analyses of DNA methylome dynamics during hematopoietic development suggest that DNA demethylation pre-defines the gene expression potential of terminal differentiation-specific genes at the progenitor cell stage and is regulated by lineage-specific transcription factors (TFs). Demethylation of majority of hypo-methylated CpGs in terminally differentiated cells occurs during the progenitor cell stage and is associated with rapid upregulation of terminal differentiation-specific genes. Accordingly, TF overrepresentation analyses indicated that lineage-specific TFs regulate DNA demethylation. The present experiments show that RUNX1 induces site-directed active DNA demethylation by recruiting DNA demethylation enzymes. Collectively, the present data indicate an integrated system of DNA methylation and gene expression during cellular development.

2017-08-10 | GSE85524 | GEO

Transcription Factors Involved in DNA Demethylation During Human Cellular Development

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2020-10-12 | PXD019794 | Pride

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Project description:The DNA methylation program is at the bottom layer of the epigenetic regulatory cascade of vertebrate development. While the methylation at C-5 position of the cytosine (C) residues on the vertebrate genomes is achieved through the catalytic activities of the DNA methyltransferases (DNMTs), the conversion of the methylated cytosine (5mC) could be accomplished by the combined actions of the TET enzyme and DNA repair. Interestingly, it has been found recently that the mouse and human DNMTs also possess active DNA demethylation activity in vitro in a Ca2+- and redox condition-dependent manner. We report here the study of tracking down the fate of the methyl group removed from 5mC on DNA during in vitro demethylation reaction by mouse de novo DNMTs, i.e. DNMT3A and DNMT3B. Remarkably, the methyl group becomes covalently linked to the catalytic cysteines utilized by the two de novo DNMTs in their DNA methylation reactions. Thus, the forward and reverse reactions of DNA methylations by the DNMTs may utilize the same cysteine residue(s) as the active site despite of their distinctive pathways. Secondly, we demonstrate that active DNA demethylation of a heavily methylated GFP reporter plasmid by ectopically expressed DNMT3A or DNMT3B occurs in vivo in transfected human HEK 293 cells in culture. Furthermore, the extent of DNA demethylation by the DNMTs in this cell-based system is affected by Ca2+ homeostasis as well as by mutation of their putative active cysteines. These findings substantiate the roles of the vertebrate DNMTs as double-edged swords in DNA methylation-demethylation in vitro as well as in a cellular context.

2022-02-24 | PXD003401 | Pride

High throughput screening identifies SOX2 as a Super Pioneer Factor that inhibits DNA methylation maintenance at its binding sites

Project description:Access of mammalian transcription factors (TFs) to regulatory regions, an essential event for transcription regulation, is hindered by chromatin compaction involving nucleosome wrapping, repressive histone modifications and DNA methylation. Moreover, methylation of TF binding sites (TBSs) affects TF binding affinity to these sites. Remarkably, a special class of TFs called pioneer transcription factors (PFs) can access nucleosomal DNA, leading to nucleosome remodelling and chromatin opening. However, whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Here, we set up a highly parallelized approach to investigate PF ability to bind methylated DNA and induce demethylation. Our results indicate that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs that have a strong pioneering activity; while most PFs do not induce changes in DNA methylation at their binding sites, we identified PFs that can protect DNA from methylation and PFs that can induce DNA demethylation at methylated binding sites. We called the latter “super pioneer transcription factors” (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Importantly, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation by inhibition of the maintenance methyltransferase DNMT1 during replication. This important finding suggests a novel mechanism allowing TFs to interfere with the epigenetic memory during DNA replication.

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Transcription Factors Involved in DNA Demethylation During Human Cellular Development

Project description:Transcription Factors Involved in DNA Demethylation During Human Cellular Development

| PRJNA720888 | ENA

A screening system to identify transcription factors that induce binding site-directed DNA demethylation

Project description:Background: DNA methylation is a fundamental epigenetic modification which is involved in many biological systems such as differentiation and disease. We and other groups recently discovered that a part of transcription factors (TFs) plays a role for site-specificity determination of DNA demethylation in a binding site-directed manner, although number of reports for such TFs are limited. Results: Here, we develop a screening system to identify TFs which induce the binding site-directed DNA methylation changes. The system consists of ectopic expression of target TFs in model cells and the DNA methylome analysis followed by overrepresentation analysis of the corresponding TF binding motif at differentially methylated regions. Our system successfully identifies binding site-directed demethylation of SPI1 which is known to promote DNA demethylation in a binding-site directed manner. We extend our screening system to 15 master TFs which are involved in cellular differentiations, and identified 8 (RUNX3, GATA2, CEBPB, MAFB, NR4A2, MYOD1, CEBPA and TBX5) novel binding site-directed DNA demethylation inducing TFs. Gene ontology and specifically expressing tissue enrichment analysis revealed that those 8 TFs demethylate genome regions which are associated with corresponding biological roles, supporting performance of our system. We also describe characteristics of the binding site-directed DNA demethylation induced by those TFs; targeting highly methylated CpGs, local DNA demethylation, and overlap of demethylated regions between same family TFs. Conclusion: Thus, our results emphasize usefulness of the developed screening system for identification of TFs which induce DNA demethylation in a site-directed manner.

2017-11-29 | GSE102822 | GEO

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