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The transcription factor Grainyhead primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes [scATAC-seq]

ABSTRACT: Transcriptional enhancers function as docking platforms for combinations of transcription factors to control gene expression. How enhancer sequences determine nucleosome occupancy, transcription factor recruitment, and transcriptional activation in vivo remains unclear. Using ATAC-seq across a panel of Drosophila inbred strains we found that SNPs affecting Grainyhead binding sites causally determine the accessibility of epithelial enhancers. We show that deletion or ectopic expression of Grh causes loss or gain of DNA accessibility, respectively. However, while Grh binding is necessary for enhancer accessibility, it is insufficient to activate enhancers. Finally, we show that human Grh homologs, GRHL1/2/3, function similarly. We conclude that Grh binding is necessary and sufficient for the opening of epithelial enhancers, but not for their activation. Our data support the model that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which pioneer factors, such as Grh, establish tissue-specific accessible chromatin landscapes upon which other factors can act.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE102544 | GEO | 2018/06/04

REPOSITORIES: GEO

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The transcription factor Grainyhead primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes [evolutionary study]

Project description:Transcriptional enhancers function as docking platforms for combinations of transcription factors to control gene expression. How enhancer sequences determine nucleosome occupancy, transcription factor recruitment, and transcriptional activation in vivo remains unclear. Using ATAC-seq across a panel of Drosophila inbred strains we found that SNPs affecting Grainyhead binding sites causally determine the accessibility of epithelial enhancers. We show that deletion or ectopic expression of Grh causes loss or gain of DNA accessibility, respectively. However, while Grh binding is necessary for enhancer accessibility, it is insufficient to activate enhancers. Finally, we show that human Grh homologs, GRHL1/2/3, function similarly. We conclude that Grh binding is necessary and sufficient for the opening of epithelial enhancers, but not for their activation. Our data support the model that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which pioneer factors, such as Grh, establish tissue-specific accessible chromatin landscapes upon which other factors can act.

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The transcription factor Grainyhead primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes [ATAC-seq]

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The transcription factor Grainyhead primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes [ATAC-seq Grh mutants and Human GRHL]

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Genome-wide identification of Grainy head targets in Drosophila [ChIP-seq]

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Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>

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LFQMS of RING2 (RING1B, RNF2) immunoprecipitation from MDA-MB-231 and T47D breast cancer cells

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GATA3 acts upstream of FOXA1 in mediating ER binding by shaping enhancer accessibility

Project description:Estrogen Receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences in enhancer occupancy by ESR1, contribute to the diverse expression profiles and clinical outcome observed in breast cancer patients. GATA3 is an ESR1 co-operating transcription factor mutated in breast tumors, however its genomic properties are not fully defined. In order to investigate the composition of enhancers involved in estrogen-induced transcription and the potential role of GATA3, we performed extensive ChIP-sequencing in unstimulated breast cancer cells and following estrogen treatment. We find that GATA3 is pivotal in mediating enhancer accessibility at regulatory regions involved in ESR1-mediated transcription. GATA3 silencing resulted in a global redistribution of co-factors and active histone marks prior to estrogen stimulation. These global genomic changes altered the ESR1 binding profile that subsequently occurred following estrogen, with events exhibiting both loss and gain in binding affinity, implying a GATA3 mediated re-distribution of ESR1 binding. The GATA3-mediated re-distributed ESR1 profile correlated with changes in gene expression, suggestive of its functionality. Chromatin loops at the TFF locus involving ESR1 bound enhancers occurred independently of ESR1 when GATA3 was silenced, indicating that GATA3, when present on the chromatin, may serve as a licensing factor for estrogen- ESR1 mediated interactions between cis-regulatory elements. Together these experiments suggest that GATA3 directly impacts ESR1 enhancer accessibility and may potentially explain the contribution of mutant-GATA3 in the heterogeneity of ESR1+ breast cancer. GATA and ER binding studied by chromatin immunoprecipitation in breast cancer cell lines, with and without estrogen stimulation and by knocking down GATA

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