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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

Project description:DNA methylation is an important epigenetic modification involved in the regulation of mammalian gene expression, with each type of cell developing a specific methylation profile during its differentiation. The enzymatic mechanisms of DNA methylation and demethylation are well understood; however, little is known about how cell-type-specific DNA methylation profiles are developed. Recently, a small subgroup of transcription factors (TFs) have been shown to promote DNA demethylation at their binding sites (e.g., RUNX1 reported by our group).

2022-03-30 | GSE171773 | GEO

ChIP-MS of DPPA3/STELLA in mouse embryonic stem cells

Project description:Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.

2020-10-12 | PXD019794 | Pride

DNA methylation during HepaRG hepatocyte differentiation

Project description:During embryonic development DNA methylation is highly dynamic, although less is known about the stability and fine-tuning of DNA methylation at later stages of differentiation. To understand the role of DNA methylation during hepatocyte differentiation, we profiled approximately 450k methylation sites at different time points in the progression from hepatoblast to hepatocyte stages using the bipotent liver progenitor HepaRG cell line. Progressive demethylation of HNF4A P1 was highly correlated with increased expression of the shorter isoforms of HNF4A. In addition, the absence of cell division at later stages of differentiation and the increased expression of TET1 and TET2 transcripts indicates that a process of active demethylation is taking place at this specific locus. These data suggest that liver progenitors are poised for targeted demethylation at specific genomic locations involved in terminal stages of hepatocyte differentiation.

2017-07-22 | GSE72074 | GEO

Active DNA Demethylation by DNMT3A and DNMT3B - Mechanistic Aspect and In Vivo Evidence

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

Transcription Factors Involved in DNA Demethylation During Human Cellular Development

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

| PRJNA720888 | ENA

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.

2021-03-18 | GSE144524 | GEO

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

Deconstruction of DNA methylation patterns during myogenesis reveals specific epigenetic events in the establishment of the skeletal muscle lineage

Project description:Cellular differentiation involves widespread epigenetic reprogramming, including modulation of DNA methylation patterns. We have investigated DNA genome-wide methylation dynamics in embryonic stem cells, primary myoblasts, terminal differentiated myotubes and mature myofibers. About 1.000 differentially methylated regions (DMRs) have been indentified during muscle-lineage determination and terminal differentiation. As a whole, muscle lineage commitment was characterized by a major gain of DNA methylation, while muscle differentiation was accompanied by loss of DNA methylation in CpG-poor regions. Notably, hypomethylated regions in muscle cells were neighboured by enhancer-type chromatin, suggesting the involvement of DNA methylation in the regulation of cell-type specific enhancers. Indeed, one of the hypomethylations detected in muscle cells affected the super-enhancer of the master transcription factor Myf5. Super-enhancers have been defined as large clusters of transcriptional enhancers driving cell-identity and gene expression, but how these lineage-specific super-enhancers are specifically activated or repressed in different tissues is not well understood. We demonstrated that the binding of the transcription factor USF1 to Myf5 locus occurs upon DNA demethylation of the super-enhancer region in myogenic committed cells. Taken all together, we have characterized the unique DNA methylation signatures of muscle-committed cells and highlighted the importance of DNA methylation mediated regulation of cell identity super-enhancers. We have investigated DNA genome-wide methylation dynamics in embryonic stem cells, primary myoblasts, terminal differentiated myotubes and mature myofibers by AIMS-seq techniques and coupled to microarray expression data by SurePrint G3 Mouse 8x60K from Agilent Technologies. Samples were in triplicates, except for ESCs (quadruplicates).

2015-01-16 | E-GEOD-65037 | biostudies-arrayexpress

A promoter DNA demethylation landscape of human hematopoietic differentiation

Project description:Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human ESCs and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1, and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34+ HSPCs and differentiated derivatives from CD34+ HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment. Total DNA isolated by standard procedures from different primary samples corresponding to healthy patients and several cell lines.

2011-09-14 | E-GEOD-30090 | biostudies-arrayexpress

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