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GRHL3 binding and the enhancer landscape are reorganized during transitions between different functional states of epidermal keratinocytes [ChIP-seq]

ABSTRACT: The genomic mechanisms underlying progressive, irreversible cell lineage commitments and differentiation, which include large scale chromatin re-organization, transcription factor binding, and chromatin modifications, have been well defined. However, we know little about the chromatin changes during transitions between transient cell states such as cell migration. Here we demonstrate the formation of unique complements of typical enhancers and super-enhancers as human progenitor keratinocytes either differentiate or migrate. Unique super-enhancers for each cellular state are linked to gene expression that confer functions associated with each cell state, and sequence variants associated with skin diseases are enriched within super-enhancers. GRHL3, a factor that promotes both differentiation and migration, exhibits prominent super-enhancer interactions in differentiating keratinocytes, while during migration, it preferentially binds to promoters along with REST, repressing the expression of migration inhibitors. Key epidermal differentiation transcription factor genes, including GRHL3, are located within super-enhancers, and many of these transcription factors in turn bind to and regulate super-enhancers. Of note, GRHL3 also represses the formation of a number of progenitor and non-keratinocyte super-enhancers in differentiating keratinocytes. Thus, coordinated GRHL3 binding and enhancer rearrangements regulate the functional states of keratinocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95199 | GEO | 2017/04/12

SECONDARY ACCESSION(S): PRJNA376403

REPOSITORIES: GEO

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GRHL3 binding and the enhancer landscape are reorganized during transitions between different functional states of epidermal keratinocytes [siREST-migration]

Project description:The genomic mechanisms underlying progressive, irreversible cell lineage commitments and differentiation, which include large scale chromatin re-organization, transcription factor binding, and chromatin modifications, have been well defined. However, we know little about the chromatin changes during transitions between transient cell states such as cell migration. Here we demonstrate the formation of unique complements of typical enhancers and super-enhancers as human progenitor keratinocytes either differentiate or migrate. Unique super-enhancers for each cellular state are linked to gene expression that confer functions associated with each cell state, and sequence variants associated with skin diseases are enriched within super-enhancers. GRHL3, a factor that promotes both differentiation and migration, exhibits prominent super-enhancer interactions in differentiating keratinocytes, while during migration, it preferentially binds to promoters along with REST, repressing the expression of migration inhibitors. Key epidermal differentiation transcription factor genes, including GRHL3, are located within super-enhancers, and many of these transcription factors in turn bind to and regulate super-enhancers. Of note, GRHL3 also represses the formation of a number of progenitor and non-keratinocyte super-enhancers in differentiating keratinocytes. Thus, coordinated GRHL3 binding and enhancer rearrangements regulate the functional states of keratinocytes.

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GRHL3 binding and the enhancer landscape are reorganized during transitions between different functional states of epidermal keratinocytes [siREST-proliferation]

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GRHL3 binding and the enhancer landscape are reorganized during transitions between different functional states of epidermal keratinocytes [siGRHL3-migration]

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GRHL3 chromatin binding and the super-enhancer landscape are reorganized in different functional states of epidermal keratinocytes

Project description:While the genomic mechanisms underlying progressive, irreversible cell lineage commitments are well-studied, we know little about the chromatin changes during transient cell states such as cell migration. Interestingly, a large number of SEs in NHEK-D and NHEK-M overlap genes encoding transcription factors with important roles in promotion of epidermal differentiation, including GRHL3, TP63, RUNX1, NOTCH3 and FOS. To test the role of these SE-associated transcription factors in a systematic manner, and to place GRHL3 in the context of other keratinocyte differentiation regulators, we used siRNAs to individually knock down GRHL3 and 50 other transcriptional regulators in NHEK-D. These transcriptional regulators were selected based on expression changes during human keratinocyte differentiation. Many have been previously implicated in epidermal differentiation in mice and humans; the genes encoding 22 of them are associated with SEs. To assess the effect of the knockdowns on keratinocyte differentiation, we monitored the expression of approximately 14,000 genes with custom-made Agilent microarrays. Among the 14,000 genes whose expression we monitored were all genes expressed in human keratinocytes and all transcriptional regulators. This 51 x 14,000 gene expression matrix provided a rich dataset to explore gene regulatory networks in epidermal differentiation.

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GRHL3 regulates the chromatin state during epidermal differentiation

Project description:The process of differentiation is tightly controlled, and such complex coordination of gene expression requires many layers of regulation. One such mechanism of regulation occurs through distal genomic regions called enhancers, which are believed to act as concentrating sites for transcription factors, like GRHL3, and other regulators, forming loops to contact promoters and enhance transcription. Active enhancers have been shown to have high levels of H3K4me1 and H3K27ac modified nucleosomes, with low levels of H3K4me3, while poised developmental enhancers have been shown to have H3K27me3 in place of H3K27ac. Additionally, in each cell type, a select few enhancers have been found to be unusually long (more than 12.5kb) and show high intensity of transcription factor binding and chromatin enhancer signature marks. These regions, termed super enhancers, are frequently tissue-specific and are thought to regulate the unique gene expression programs in each tissue. ChIP-Seq analysis revealed GRHL3 binding to be strongly enriched within enhancers and super enhancers in differentiating keratinocytes, however the effect of GRHL3 binding on enhancer and super enhancer activity and function is not known.

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Analysis of gene expression in differentiated human primary keratinocytes depleted for Grainyhead like 3 (GRHL3)

Project description:Human primary keratinocytes were depleted of GRHL3 by siRNA and induced to differentiated for 2 days by addition of Calcium Primary normal human keratinocytes were transfected with GRHL3 or scrambled control siRNA using RNAi max (Life Technologies). 24 hours post transfection medium was raised to 1.8mM to induce differentiation. Cells were collected 48 hours later.

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Genome-wide binding of WDR5 and GRHL3

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2012-11-10 | E-GEOD-42180 | biostudies-arrayexpress

Analysis of gene expression in differentiated human primary keratinocytes depleted for Grainyhead like 3 (GRHL3)

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Project description:The transcriptional basis for disrupted epidermal differentiation arising from TP63 AEC mutations remains to be elucidated. Here we present an organotypic model of AEC dysfunction that phenocopies differentiation defects observed in AEC patient skin. Transcriptional analysis of model AEC tissue revealed impaired induction of differentiation regulators, including OVOL1, GRHL3, KLF4, PRDM1 and ZNF750. Genome wide binding analyses of TP63 during epidermal differentiation showed direct binding of OVOL1, GRHL3, and ZNF750 promoters suggesting AEC mutants prevent normal activation of these targets by direct transcriptional interference. Remarkably, exogenous ZNF750 restores impaired epidermal differentiation caused by AEC mutation. Thus, repression of ZNF750 is central to disrupted epidermal differentiation in model AEC tissue. ChIP-Seq analysis: Examination of p63 binding in proliferating and differentiating human keratinocytes

2012-06-18 | E-GEOD-33571 | biostudies-arrayexpress

Gene expression data of human primary keratinocytes with control, EXOSC9 or EXOSC9+GRHL3 knockdown

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