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Loss of DNMT3A/B in human ES cells triggers increased cell-cell variability and transcriptional repression

ABSTRACT: Maintenance of human pluripotent stem cells is dependent on extrinsic signals and cross talk between transcriptional and epigenetic regulators. Methylation of cytosines through the de novo methyltransferases DNMT3A and 3B plays an important role for exiting pluripotency and facilitating proper differentiation. Here, we generated and analyzed single cell expression data from wild-type and DNMT3A/B knockout human embryonic stem cells to better understand the precise effects on pluripotency and differentiation. Although DNA methylation is generally associated with gene silencing, we find unexpected and widespread transcriptional repression upon loss of DNMT3A or DNMT3A/3B. Furthermore, the transcriptional misregulation in DNMT3A knockout cells is largely propagated during differentiation towards mesoderm. Additionally, we observe increased cellular and transcriptional heterogeneity in undifferentiated cells upon deactivation of DNMTs as well as a notable change in cell cycle gene expression. Taken together, our single-cell RNA sequencing data provides several new insights into the role of DNA methylation in human pluripotent stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134483 | GEO | 2019/08/30

REPOSITORIES: GEO

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Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation. This model is described in the article: In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach. Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R BMC Genomics, 2009, 10:314 Abstract: BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency. RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation. CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies. This model is hosted on BioModels Database and identified by: MODEL1305010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Loss of DNMT3A/B in human ES cells triggers increased cell-cell variability and transcriptional repression

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