Similar Datasets
Project description:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.
| S-EPMC6030064 | biostudies-literature
Project description:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific cell lineage, changes in histone modifications and DNA methylation accompany the transition to more specialized cell types. Investigating how epigenetic regulation maintains pluripotency is a critical component in order to generate the required cell types for future clinical application. Uhrf1 is a widely known hemi-methylated DNA binding protein, playing a role in heterochromatin formation alongside G9a, Trim28 and HDACs. In addition, it has been demonstrated that Uhrf1 functions to maintain DNA methylation through the recruitment of Dnmt1. Although Uhrf1 is not essential in ESC self-renewal, it still remains elusive how Uhrf1 regulates pluripotency. Here, we set out to elucidate the role of Uhrf1 in pluripotent stem cells. We found that Uhrf1 forms a complex with the active trithorax group of transcriptional regulators, in particular the Setd1a/COMPASS complex. Our data show that loss of Uhrf1 causes a dramatic reduction of bivalent histone marks, in particular those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards the balance between pluripotency and differentiation via the Setd1a/COMPASSS complex, through which Uhrf1 mediates bivalent histone modifications.
2018-05-02 | GSE113914 | GEO
Project description:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific cell lineage, changes in histone modifications and DNA methylation accompany the transition to more specialized cell types. Investigating how epigenetic regulation maintains pluripotency is a critical component in order to generate the required cell types for future clinical application. Uhrf1 is a widely known hemi-methylated DNA binding protein, playing a role in heterochromatin formation alongside G9a, Trim28 and HDACs. In addition, it has been demonstrated that Uhrf1 functions to maintain DNA methylation through the recruitment of Dnmt1. Although Uhrf1 is not essential in ESC self-renewal, it still remains elusive how Uhrf1 regulates pluripotency. Here, we set out to elucidate the role of Uhrf1 in pluripotent stem cells. We found that Uhrf1 forms a complex with the active trithorax group of transcriptional regulators, in particular the Setd1a/COMPASS complex. Our data show that loss of Uhrf1 causes a dramatic reduction of bivalent histone marks, in particular those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards the balance between pluripotency and differentiation via the Setd1a/COMPASSS complex, through which Uhrf1 mediates bivalent histone modifications.
2018-05-02 | GSE113913 | GEO
Project description:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific cell lineage, changes in histone modifications and DNA methylation accompany the transition to more specialized cell types. Investigating how epigenetic regulation maintains pluripotency is a critical component in order to generate the required cell types for future clinical application. Uhrf1 is a widely known hemi-methylated DNA binding protein, playing a role in heterochromatin formation alongside G9a, Trim28 and HDACs. In addition, it has been demonstrated that Uhrf1 functions to maintain DNA methylation through the recruitment of Dnmt1. Although Uhrf1 is not essential in ESC self-renewal, it still remains elusive how Uhrf1 regulates pluripotency. Here, we set out to elucidate the role of Uhrf1 in pluripotent stem cells. We found that Uhrf1 forms a complex with the active trithorax group of transcriptional regulators, in particular the Setd1a/COMPASS complex. Our data show that loss of Uhrf1 causes a dramatic reduction of bivalent histone marks, in particular those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards the balance between pluripotency and differentiation via the Setd1a/COMPASSS complex, through which Uhrf1 mediates bivalent histone modifications.
2018-05-02 | GSE113912 | GEO
Project description:Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a
| PRJNA454457 | ENA
Project description:Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a [RNA-Seq]
| PRJNA454459 | ENA
Project description:Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a [ChIP-Seq]
| PRJNA454460 | ENA
Project description:Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a [ATAC-Seq]
| PRJNA454458 | ENA
Project description:Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer.
| S-EPMC9771694 | biostudies-literature
Project description:Silencing of multiple cancer-related genes is associated with de novo methylation of linked CpG islands. Additionally, bivalent histone modification profiles characterized by the juxtaposition of active and inactive histone marks have been observed in genes that become hypermethylated in cancer. It is unknown how these ambiguous epigenetic states are maintained and how they interrelate with adjacent genomic regions with different epigenetic landscapes. Here, we present the analysis of a set of neighboring genes, including many frequently silenced in colon cancer cells, in a chromosomal region at 5q35.2 spanning 1.25 Mb. Promoter DNA methylation occurs only at genes maintained at a low transcriptional state and is characterized by the presence of bivalent histone marks, namely trimethylation of lysines 4 and 27 in histone 3. Chemically induced hyperacetylation and DNA demethylation lead to up-regulation of silenced genes in this locus yet do not resolve bivalent domains into a domain-wide active chromatin conformation. In contrast, active genes in the region become down-regulated after drug treatment, accompanied by a partial loss of chromatin domain boundaries and spreading of the inactive histone mark trimethylated lysine 27 in histone 3. Our results demonstrate that bivalent domains mark the promoters of genes that will become DNA methylated in adult tumor cells to enforce transcriptional silence. These bivalent domains not only remain upon drug induced gene reactivation, but also spread over adjacent CpG islands. These results may have important implications in understanding and managing epigenetic therapies of cancer.
| S-EPMC2596747 | biostudies-literature