Expression data from pre-iPSCs with a control, histone methyltransferase or Cbx3 (HP1g) knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Rupa Sridharan
PROVIDER: E-GEOD-44084 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We examined the locations of Cbx3 by chromatin immunoprecipitation in ESCs and pre-iPSCs Examination of Cbx3 in mESC (mouse embryonic stem cells) and pre-iPSCs (fibroblast derived partially reprogrammed cells)
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Project description:The methylation of histone 3 at lysine 9 (H3K9) is widely regarded as a major roadblock for cellular reprogramming and interference with associated methyltransferases such as EHMT1 and EHMT2 (also known as GLP and G9A) facilitates the derivation of induced pluripotent stem cells (iPSCs). In addition, activation of demethylases by ascorbic acid (AA) has become a common approach to facilitate the extensive epigenetic remodeling required for iPSC formation. The functional interaction between the H3K9 methylation machinery and AA-stimulated enzymes, and consequences of interfering with these pathways, remain insufficiently explored. Here, we show that reduction of EHMT1/2 activity paradoxically counteracts iPSC formation in an optimized reprogramming system in the presence of AA. At the cellular and molecular level, EHMT1/2 activity is required for efficient downregulation of somatic genes and transition into an epithelial state. Genetic interference with the demethylase KDM3B partially rescues the adverse effect of EHMT1/2 inhibition on iPSC formation. Transient inhibition of EHMT1/2 during reprogramming yields iPSCs that fail to efficiently give rise to viable mice, suggesting persistent molecular defects in these cells. Together, our observations document a more nuanced function of H3K9 methyltransferases during iPSC formation and suggest that the balancing of AA-stimulated enzymes by EHMT1/2 is required for efficient and error-free reprogramming to pluripotency.
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Project description:EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2 cKO, Ehmt1cKO, Ehmt1/2 cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1 cKO and Ehmt1/2 cDKO oocytes recapitulated meiotic defects observed in the Ehmt2 cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1 cKO and Ehmt1/2 cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2 cDKO than Ehmt2 cKO oocytes, withtranscriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2 cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence
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Project description:We investigated genome-wide nucleosome coverage and histone methylation occupancies in somatic MEFs, intermediate pre-iPSCs and fully reprogrammed iPSCs. We found that nucleosome occupancies increased in promoter regions and decreased in intergenic regions in pre-iPSCs and then recover to an intermediate level in iPSCs. Nucleosomes in pre-iPSCs are much more phased than those in MEFs and iPSCs. Bivalent, active, repressive domains are cell type-specific and change dynamically during reprogramming. HCG and LCG promoters exhibit distinct nucleosome occupancy patterns and are dynamically marked by H3K4me3/H3K27me3 during reprogramming, correspondingly showing different gene activities. Surprisingly, Vitamin C promotes nucleosome reorganization from pre-iPSCs to iPSCs. CTCF binding sites change dynamically during reprogramming, though they share a conserved binding motif. Nucleosome occupies CTCF sites to a higher extent in pre-iPSCs than those in MEFs and iPSCs. Taken together, our study reveals that dynamic changes of nucleosome positioning and chromatin organization associated gene regulation during reprogramming. Examine dynamics of nucleosome positioning and histone modification profiles as well as gene expression regulation during somatic cell reprogramming
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Project description:We examined the locations of Cbx3 by chromatin immunoprecipitation in ESCs and pre-iPSCs
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Project description:Cbx3 (HP1γ) that is a member of the heterochromatin protein 1 familiy enriched in gene bodies of pluripotent ESCs but promoters of differentiated pre-iPSCs. To determine whether Cbx3 becomes enriched at promoters to influence gene regulation during differentiation, we converted ESCs to NPCs in monolayer culuture and performed genomewide ChIP-seq of Cbx3. Our results shows that Cbx3 enriches at the promoters of genes upon differentiation of ESCs to NPCs and stablizes the binding of Mediator subunit Med26 to pre-initiation complex (PIC) in NPCs.
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Project description:Transition from a partially reprogrammed pre-iPSC state to iPSC state can be achieved by modulating levels of histone modifying enzymes or proteins that can bind to histone modifications We used microarrays to determine the gene expression profile of pre-iPSCs depleted for either 3 histone methyltransferases together or the HP1gamma protein
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Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma, wherein the malignant tumors arise from the myoblast like cells due to the perturbations in growth and differentiation. Alveolar rhabdomyosarcoma (ARMS) is one of the two major histological subtypes which exhibits high metastatic potential and tumor recurrence culminating in poor prognosis. In the recent past, understanding the epigenetic modifications in these tumors with less genetic alterations has shed light on the process of tumor pathogenesis and development of potential epi-drugs for the effective treatment strategies. Epigenetic regulator, Euchromatin histone lysine methyltransferase 1 (EHMT1)/G9A-like protein (GLP) and its homolog Euchromatin histone lysine methyltransferase 1 (EHMT2)/G9A has been shown to promote proliferation and inhibit differentiation in the mouse myoblast cells, independently. Also, previous study from our lab reported the overexpression of EHMT2 and molecular mechanism associated with the oncogenic phenotype in ARMS. However, expression pattern and functional role of EHMT1 in ARMS is unknown. Herein, we investigated the role of EHMT1 in ARMS. Our preliminary data indicated the overexpression of EHMT1 and the associated oncogenic phenotypes in ARMS. Although EHMT1 has shown to be upregulated and correlated with the increased disease severity in several cancers including gastric, esophagus, squamous cell carcinoma, ovarian and breast cancer, the mechanism involved in the EHMT1 mediated tumorigenesis was unclear. Therefore, through our current study we aimed to understand the expression pattern and the mechanism through which EHMT1 regulated cancer phenotypes in ARMS, for this we performed whole transcriptomic analysis in ARMS cell lines upon EHMT1 knockdown for the first time. In addition, we also compared the expression levels of EHMT1 between Human skeletal muscle myoblasts (HSMM) and ARMS patient samples (obtained from St Jude cloud database).
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