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Defining a critical Nanog enhancer using chromatin-focused approaches identifies RNAPII recruitment as required for expression [ATAC-Seq]

ABSTRACT: Transcriptional enhancers have been defined by their ability to operate independent of distance and orientation in plasmid reporter assays, rather than within native chromatin. We employed a combination of approaches to investigate the Nanog locus in mouse embryonic stem cells (ESCs) and an associated cis regulatory element (CRE) which may operate as a super-enhancer (SE) or alternative promoter. We establish the element is a SE within chromatin using distance- and orientation-independence as criteria. We next demonstrate this SE regulates Nanog by recruiting and/or initiating RNA Polymerase II. Our work highlights that enhancers likely operate through a diverse set of mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE149531 | GEO | 2020/12/07

REPOSITORIES: GEO

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Defining a critical Nanog enhancer using chromatin-focused approaches identifies RNAPII recruitment as required for expression [-5delRNASeq]

Project description:Transcriptional enhancers have been defined by their ability to operate independent of distance and orientation in plasmid reporters rather than native chromatin. We employed a combination of approaches to investigate the Nanog locus in mouse embryonic stem cells (ESCs) and an associated cis regulatory element (CRE) which may operate as either a super-enhancer (SE) or alternative promoter. We establish this element is a SE within chromatin using distance- and orientation-independence as criteria, and that it regulates Nanog by recruiting and/or initiating RNA Polymerase II. Our work highlights that enhancers can regulate gene expression through a diverse set of mechanisms.

2020-12-07 | GSE143959 | GEO

Defining a critical Nanog enhancer using chromatin-focused approaches identifies RNAPII recruitment as required for expression [CUT&Tag]

2020-12-07 | GSE143991 | GEO

Two super-enhancers regulate Nanog expression through distinct mechanisms [45del]

Project description:Enhancers are critical regulators of gene expression which are historically defined using plasmid-based approaches. Recent work has emphasized that enhancers operate by alleviating promoter-proximal pause release, implying that a single enhancer operates on a gene at any given moment. By contrast, our previous work postulated that two super-enhancers (SEs) may simultaneously operate on a single gene. To address this discrepancy we employed genomic editing, single cell analyses, and genome-wide approaches to assess how two SEs regulate Nanog expression in embryonic stem cells. We first demonstrate both distance and orientation independence in native chromatin, eliminating the issues raised with plasmid-based approaches. We also demonstrate that two SEs simultaneously operate on Nanog by regulating different phases of transcription, with one SE operating by recruiting and/or initiating RNA Polymerase II, and the second promoting transcriptional elongation after promoter-proximal pause release. These findings imply SEs can use different mechanisms to regulate expression.

2021-01-10 | GSE143960 | GEO

Discovery of NANOG enhancers and their essential roles in self-renewal and differentiation in human embryonic stem cells

Project description:Human embryonic stem cells (hESCs) are an important system to study development and regeneration. NANOG is a core regulator in hESCs, but it is transcriptionally regulated is not fully understood. In this study, we report the discovery of two NANOG enhancers from a CRISPR interference enhancer screen in hESCs. These enhancers are essential to hESCs, and deletion of a single copy of either enhancers significantly reduced NANOG expression. In addition, hESCs with heterozygous deletion of either enhancers had compromised self-renewal and increased tendency to differentiate. Interestingly, these two NANOG enhancers are involved in a tandem duplication event, but the duplicated counterparts do not regulate NANOG. This work expands our knowledge of functional enhancers in hESCs, and highlights the sensitivity of the hESC state to the dosage of a core regulator.

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Two super-enhancers regulate Nanog expression through distinct mechanisms [45del]

Project description:Two super-enhancers regulate Nanog expression through distinct mechanisms [45del]

| PRJNA602332 | ENA

Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition

Project description:Transcriptional enhancers, including super-enhancers (SE), form physical interactions with promoters to regulate cell type-specific gene expression. SE are characterised by high transcription factor occupancy and large domains of active chromatin, and are currently assigned to target promoters using computational predictions. How promoter–SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, has not been reported. Here, we used promoter-capture Hi-C to identify promoters in close physical proximity to SE in mouse embryonic stem cells (ESCs). SE form complex, spatial networks in which individual SE contact multiple promoters, and a rewiring of promoter–SE interactions occurs between ESC and EpiSC pluripotent states. Long-range promoter–SE interactions are a hallmark of ESCs and are dependent on the transcription factor NANOG. These results provide new insights into the gene regulatory organization of pluripotent cells and demonstrate the requirement for transcription factors in maintaining a subset of SE interactions.

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Gene expression signatures for Nanog-positive and Nanog-negative hepatocellular carcinoma cells

Project description:Whole genome microarray expression profiling of HCC cell line (Huh7) and patients derive primary HCC cells (T1115 and T1224) expressing Nanog or not. Results provide insight into the role of Nanog in transcriptional regulation.

2014-11-13 | GSE33741 | GEO

Nanog-induced intestinal and colonic hyperplasia

Project description:Though expression of the homeobox transcription factor Nanog is generally restricted to pluripotent cells and early germ cells, recent reports have found that Nanog is re-expressed in somatic and germ cell tumors associated with poor differentiation and aggressive disease progression. To elucidate its oncogenic properties, a modified Tet-On system was utilised to generate Nanog-inducible mice. By dexamethasone and doxycycline injection, similar Nanog expression levels as in wild-type embryonic stem cells were obtained in all major organs except for brain. Ectopic Nanog expression resulted in intestinal and colonic epithelium hyperplasia-intestinal villi had doubled in length and hyperplastic epithelium outgrowths were seen after 7 days. The tumor suppressor gene Cdx2 was downregulated at onset of Nanog expression, suggesting that crosstalk between Nanog and Cdx2 is conserved from early embryo development to adulthood. Although the mice died before they could form tumors, Cdx2 repression and intestinal hyperplasia links Nanog to tumor initiation.

2014-08-11 | GSE31413 | GEO

Nanog-induced intestinal and colonic hyperplasia

2014-08-11 | E-GEOD-31413 | biostudies-arrayexpress

NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers

Project description:Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGC) in mice1, where its precise role is yet unclear2-4. We investigated this in an in vitro model, where naÃ¯ve pluripotent embryonic stem cells (ESCs) cultured in bFGF/ActivinA develop as epiblast-like cells (EpiLCs), and gain competence for PGC-like fate5. Consequently, bone morphogenetic protein (BMP4), or ectopic expression of key germline transcription factors Prdm1/ Prdm14/ Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ESCs6-8. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that following the dissolution of the naÃ¯ve ESC pluripotency network during establishment of EpiLCs9,10, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG binding pattern between ESCs and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ESCs, they show contrasting roles in EpiLCs since Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development. Refer to individual Series

2016-01-11 | E-GEOD-71933 | biostudies-arrayexpress

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