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RNA Sequencing of H1 WT hESCs, H1 QSER1 KO hESCs, H1 TET1 KO hESCs, H1 QSER1/TET1 DKO hESCs, WT Day10 EBs, QSER1 KO Day10 EBs, TET1 KO Day10 EBs, QSER1/TET1 DKO Day10 EBs, WT PP1, QSER1 KO PP1, TET1 KO PP1, and QSER1/TET1 DKO PP1.

ABSTRACT: RNA Sequencing of H1 WT hESCs, H1 QSER1 KO hESCs, H1 TET1 KO hESCs, H1 QSER1/TET1 DKO hESCs, WT Day10 embryoid bodies (EBs), QSER1 KO Day10 EBs, TET1 KO Day10 EBs, QSER1/TET1 DKO Day10 EBs, WT pancreatic progenitors (PP1), QSER1 KO PP1, TET1 KO PP1, and QSER1/TET1 DKO PP1. DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to tightly regulate the methylation landscape remains a central question. Utilizing a knockin DNA methylation reporter, we performed a genome-wide CRISPR/Cas screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate cooperation of QSER1 and TET1 through genetic and biochemical interactions to inhibit DNMT3-mediated de novo methylation and safeguard developmental programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169209 | GEO | 2021/03/19

REPOSITORIES: GEO

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Project description:The ability of cells to perceive and translate versatile cues into differential chromatin and transcriptional states is critical for many biological processes1-4. In plants, timely transition to a flowering state is crucial for successful reproduction5-7. EARLY BOLTING IN SHORT DAY (EBS) is a negative transcriptional regulator that prevents premature flowering in Arabidopsis8,9. Here, we revealed that bivalent bromo-adjacent homology (BAH)-plant homeodomain (PHD) reader modules of EBS bind H3K27me3 and H3K4me3, respectively. A subset of EBS-associated genes was co-enriched with H3K4me3, H3K27me3, and the Polycomb repressor complex 2 (PRC2). Interestingly, EBS adopts an auto-inhibition mode to mediate its binding preference switch between H3K27me3 and H3K4me3. This binding balance is critical because disruption of either EBS-H3K27me3 or EBS-H3K4me3 interaction induces EBS-mediated early floral transition. This study identifies a single bivalent chromatin reader capable of recognizing two antagonistic histone marks and reveals a distinct mechanism of interplay between active and repressive chromatin states.The ability of cells to perceive and translate versatile cues into differential chromatin and transcriptional states is critical for many biological processes1-4. In plants, timely transition to a flowering state is crucial for successful reproduction5-7. EARLY BOLTING IN SHORT DAY (EBS) is a negative transcriptional regulator that prevents premature flowering in Arabidopsis8,9. Here, we revealed that bivalent bromo-adjacent homology (BAH)-plant homeodomain (PHD) reader modules of EBS bind H3K27me3 and H3K4me3, respectively. A subset of EBS-associated genes was co-enriched with H3K4me3, H3K27me3, and the Polycomb repressor complex 2 (PRC2). Interestingly, EBS adopts an auto-inhibition mode to mediate its binding preference switch between H3K27me3 and H3K4me3. This binding balance is critical because disruption of either EBS-H3K27me3 or EBS-H3K4me3 interaction induces EBS-mediated early floral transition. This study identifies a single bivalent chromatin reader capable of recognizing two antagonistic histone marks and reveals a distinct mechanism of interplay between active and repressive chromatin states.v

Dataset Information

RNA Sequencing of H1 WT hESCs, H1 QSER1 KO hESCs, H1 TET1 KO hESCs, H1 QSER1/TET1 DKO hESCs, WT Day10 EBs, QSER1 KO Day10 EBs, TET1 KO Day10 EBs, QSER1/TET1 DKO Day10 EBs, WT PP1, QSER1 KO PP1, TET1 KO PP1, and QSER1/TET1 DKO PP1.

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