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| Status |
Public on Apr 13, 2022 |
| Title |
TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We generated TET single-, double-, and triple-knockout hESCs and differentiated them towards the pancreatic endocrine fate. Two replicates were used for sequencing. We performed RNA-seq for WT and TET triple deficient lines (clone 2 and clone 6) of hESC, definitive endoderm (DE) and pancreatic progenitor (PP), as well as TET1 single-deficient line of PP. We performed WGBS (one replicate), CMS-IP, ATAC, H3K4me1, H3K27ac ChIP-seq data for WT and TET triple deficient lines. One replicate of WT TET1 ChIP-seq were also sequenced.
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| Contributor(s) |
Li J, Wu X, Ke J, Lee M, Lan Q, Li J, Huang Y, Sun D, Xie R |
| Citation(s) |
35798741 |
| Submission date |
Mar 05, 2020 |
| Last update date |
Jul 14, 2022 |
| Contact name |
Jianfang Li |
| E-mail(s) |
jianfanglee003@gmail.com
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| Organization name |
Texas A&M University
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| Street address |
2121 W. Holcombe Boulevard
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| City |
Houston |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (3) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL23227 |
BGISEQ-500 (Homo sapiens) |
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| Samples (65)
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| Relations |
| BioProject |
PRJNA610653 |
| SRA |
SRP251780 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE146486_RAW.tar |
125.0 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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