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Modular regulation of Myc transcription by a topologically defined enhancer cluster dedicated to pluripotency and early embryonic expression [4C-seq]

ABSTRACT: The transcription factor MYC plays essential roles in pluripotent stem cells, including the promotion of somatic cell reprogramming to pluripotency and the regulation of cell competition and embryonic diapause; however, how Myc expression is regulated in this context remains unknown. The Myc gene lies within a ~3-megabase gene desert that contains multiple cisregulatory elements. We used large-scale genomic deletions/inversions, BAC transgenesis and nested deletion of regulatory regions to characterize the cis-regulation of Myc transcription in the early mouse embryo and Embryonic Stem Cells (ESCs). We identified an Early Embryonic Expression (EEE) topologically-associated region that homes enhancers dedicated to Myc transcriptional regulation in stem cells of the early embryo, including the pluripotent cells of the inner cell mass, pre-implantation and post-implantation epiblast and other early embryonic stem cell populations. Within this region, we identified elements exclusively dedicated to Myc regulation in pluripotent cells, with distinct enhancers that sequentially regulate Myc ranscription during naive and formative pluripotency. Deletion of these pluripotency-specific enhancers dampens the competitive ability of ESCs. These results identify a topologically defined enhancer cluster dedicated to early embryonic expression and uncover a modular mechanism for the regulation of Myc expression in different states of pluripotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE222294 | GEO | 2024/03/06

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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Modular regulation of Myc transcription by a topologically defined enhancer cluster dedicated to pluripotency and early embryonic expression [4C-seq]

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