TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
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ABSTRACT:
PROVIDER: PRJNA610653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11248434_1.fastq.gz | Fastqsanger.gz | |||
| SRR11248434_2.fastq.gz | Fastqsanger.gz | |||
| SRR11248435_1.fastq.gz | Fastqsanger.gz | |||
| SRR11248435_2.fastq.gz | Fastqsanger.gz | |||
| SRR11248436_1.fastq.gz | Fastqsanger.gz |
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Project description:Current knowledge about the role of epigenetic modifiers in pancreas development has been exponentially increased. However, the precise function of TET dioxygenases in pancreas specification remains poorly understood. Using a stepwise human embryonic stem cell (hESC) differentiation system, TET1/TET2/TET3 triple-knockout (TKO) cells displayed severe defects in pancreatic differentiation. Whole-genome analysis revealed TET depletion led to aberrant DNA methylation and chromatin remodeling. In comparison with methylome and hydroxymethylome datasets previously generated from hESCs, we identified unique pancreas-specific hyper-methylated and hypo-hydroxymethylated regions in TKO cells, where binding of pioneer transcription factor FOXA2 was remarkably enriched. Interestingly, transduction of full-length TET1 in TKO cells effectively rescued pancreatic differentiation and the expression of PAX4, a key determinant for -cell specification. Taking these findings together with genome-wide mapping of TET1 in pancreatic progenitors, we uncovered that TET1 co-occupied at a specific subset of FOXA2-bound loci featuring high levels of active chromatin. Locus-specific DNA methylation analysis revealed significant increases of 5-methylcytosine at the PAX4 enhancer in a TET1-dependent manner, consistent with defective generation of functional beta-cells from TET1-knockout hESCs. Thus, our study not only highlights the importance of TET-dependent epigenetic regulation in pancreas development but also unveils an essential role of TET1 in establishing beta-cell identity.
2022-04-13 | GSE146486 | GEO
Project description:Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knockout cells display severe defects in pancreatic β-cell specification. The integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at the pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding feature low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-length TET1 but not the TET1-catalytic-domain in TET-deficient cells effectively rescues β-cell differentiation accompanied by restoring PAX4 hypomethylation. Taking these findings together with the defective generation of functional β-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing β-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.
| S-EPMC9263144 | biostudies-literature
Project description:Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone posttranslational modification, how oncogenic signaling remodels DNA methylation remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancer. Here we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and diseases.
2022-05-09 | GSE178227 | GEO
Project description:Epigenetic pathways that regulate DNA methylation and chromatin modifications are frequently found to be dysregulated in human cancers. The TET methylcytosine dioxygenase 1 (TET1) enzyme is an important regulator of hydroxymethylcytosine (5hmC) in embryonic stem cells, neural progenitors,adult cells and reprogrammed cells. Decreased expression of TET proteins and loss of 5hmC has been reported in many tumors, suggesting a critical role for the maintenance of this epigenetic modification in normal cellular function. However, loss of TET1 function in the etiology of cancer has not been directly investigated. Here, we show that deletion of the Tet1 gene promotes the development of B cell lymphoma. Tet1 is required for maintaining normal levels of 5hmC, preventing aberrant DNA hypermethylation and for the regulation of transcriptional programs involved in B-cell lineage specification, chromosome maintenance, and DNA repair. Progenitor B cells in the absence of Tet1 accumulate DNA damage and whole-exome sequencing of Tet1-deficient tumors revealed a high correlation of mutations with those most frequently found in Non-Hodgkin B cell lymphoma (B-NHL) patients. In addition, we show that the TET1 gene is deleted, hypermethylated and transcriptionally silenced in B-NHL patients. These findings provide the first in vivo evidence of TET1 function as a tumor suppressor of hematopoietic malignancy. We did hydroxymethylation tests for two wild type mice and two Tet1 knockout mice.
2015-04-12 | E-GEOD-65895 | biostudies-arrayexpress
Project description:FOXA1 is a FKHD family protein that translates epigenetic signatures at target enhancers to lineage-specific transcription and differentiation. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of this epigenetic signature, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically, this involves TET1, a 5-methylcytosine dioxygenase. We found that FOXA1 induces TET1 expression via direct binding at its cis-regulatory elements. Further, FOXA1 physically interacts with the TET1 protein through its CXXC domain. TET1 thus co-occupies FOXA1-dependent enhancers and mediates local DNA demethylation and concomitant histone 3 lysine 4 methylation, further potentiating FOXA1 recruitment. FOXA1 binding events were markedly reduced following TET1 depletion. Together, our results support that FOXA1 is not only a reader, but also a writer, of the epigenetic signatures at lineage-specific enhancers and that TET1 and FOXA1 form a feed-forward regulatory loop for enhancer activation. ChIP-Seq examination of FOXA1 binding sites in LNCaP cell, and epigenetic markers (5mC, 5hmC, H3K4me2) profiling upon TET1 depletion
2016-07-22 | E-GEOD-73363 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Four samples (Four samples, Hypoxia (scrambled control), Hypoxia (TET1-si), Normoxia (scrambled control) and Normoxia (TET1-si), are performed by RNA-Seq and hMeDIP-Seq
2014-08-01 | E-GEOD-59989 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Four samples (Four samples, Hypoxia (scrambled control), Hypoxia (TET1-si), Normoxia (scrambled control) and Normoxia (TET1-si), are performed by RNA-Seq and hMeDIP-Seq RNA-Seq and hMeDIP-Seq
2014-08-01 | E-GEOD-59987 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes.
2014-08-01 | GSE59989 | GEO
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes.
2014-08-01 | GSE59987 | GEO
Project description:FOXA1 is a FKHD family protein that translates epigenetic signatures at target enhancers to lineage-specific transcription and differentiation. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of this epigenetic signature, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically, this involves TET1, a 5-methylcytosine dioxygenase. We found that FOXA1 induces TET1 expression via direct binding at its cis-regulatory elements. Further, FOXA1 physically interacts with the TET1 protein through its CXXC domain. TET1 thus co-occupies FOXA1-dependent enhancers and mediates local DNA demethylation and concomitant histone 3 lysine 4 methylation, further potentiating FOXA1 recruitment. FOXA1 binding events were markedly reduced following TET1 depletion. Together, our results support that FOXA1 is not only a reader, but also a writer, of the epigenetic signatures at lineage-specific enhancers and that TET1 and FOXA1 form a feed-forward regulatory loop for enhancer activation.
2016-07-22 | GSE73363 | GEO