FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity
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ABSTRACT:
PROVIDER: PRJNA511882 | ENA |
REPOSITORIES: ENA
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Project description:Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set of FoxA binding sites that undergo regional, FoxA-dependent demethylation during organ development. Conditional ablation of FoxA genes in the adult liver demonstrated that continued FoxA presence was not required to maintain the hypomethylated state, even when massive cell proliferation was induced. This study provides strong evidence for the stable, epigenetic nature of tissue-specific DNA methylation patterns directed by lineage-determining transcription factors during organ development.
2021-04-20 | GSE124384 | GEO
Project description:Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set of FoxA-binding sites that undergo regional, FoxA-dependent demethylation during organ development. Conditional ablation of FoxA genes in the adult liver demonstrated that continued FoxA presence was not required to maintain the hypomethylated state, even when massive cell proliferation was induced. This study provides strong evidence for the stable, epigenetic nature of tissue-specific DNA methylation patterns directed by lineage-determining transcription factors during organ development.
| S-EPMC8129911 | biostudies-literature
Project description:Targeted intragenic demethylation initiates chromatin rewiring for gene activation
| PRJNA643240 | ENA
Project description:FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex network thought to become resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for this regulatory network, we ablated all FoxA genes in the adult liver. Remarkably, loss of FoxA caused a rapid and massive reduction in the expression of key liver genes back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining chromatin activity, nucleosome positioning and binding by other hepatic transcription factors. Thus, the hepatic gene regulatory network is dependent on the FoxA proteins throughout life.
2020-07-10 | GSE140423 | GEO
Project description:Aberrant Transcription Start Site (TSS) surrounding region DNA methylation is a hallmark of gene silencing in cancer. Currently approved demethylating agents lack specificity and exhibit high toxicity. Herein we show, using the p16 gene locus as an example, that targeted demethylation of the exon 1-intron 1 region initiates an epigenetic wave of local chromatin remodeling and distal long-range interactions, culminating in gene-locus specific activation. Through development of CRISPR-DiR (DNMT1-interacting RNA), an innovative technology wherein ad-hoc edited guides block methyltransferase activity in a locus-specific fashion, we demonstrate that demethylation is coupled to epigenetic and topological changes. These results suggest the existence of a specialized “demethylation firing center (DFC)” which can be switched on by an adaptable and selective RNA-mediated approach for locus-specific transcriptional activation.
2024-12-13 | GSE153563 | GEO
Project description:In the HBV transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections which are responsible for approximately one million deaths annually worldwide.
2024-07-16 | GSE263120 | GEO
Project description:In the HBV transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections which are responsible for approximately one million deaths annually worldwide.
2024-07-16 | GSE263033 | GEO
Project description:Gender-specific post-natal demethylation and establishment of epigenetic memory
| PRJNA257275 | ENA
Project description:FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: First, FOXA facilitate signal-dependent lineage initiation via enhancer priming, and second, FOXA enforce organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.
2021-10-18 | GSE148368 | GEO
Project description:Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires AID-mediated downregulation of UHRF1 protein and abolishing demethylation leaves thousands of hypermethylated regions in the iPSCs genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.
2017-01-27 | GSE69823 | GEO