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Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells

ABSTRACT: Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression. It is a mystery how chromatin marks in regulatory elements are modulated to establish cell type-specific gene expression. Here we profiled a variety of epigenetic marks in the regulatory elements using massive ChIP-seq (n=84). We uncovered two classes of regulatory elements: Class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas Class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. For common genes regulated by both promoters and enhancers, Class I promoters displayed dominant regulatory effects on transcriptional abundance. Moreover, human iPSCs and somatic cells selected their preferential regulatory elements to maintain cell type-specific gene expression. Our study provides valuable resources for deciphering the epigenetic modulation of regulatory elements that fine-tune spatiotemporal gene expression in human development and diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97033 | GEO | 2017/12/04

SECONDARY ACCESSION(S): PRJNA380431

REPOSITORIES: GEO

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Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.

Project description:Eukaryotic gene regulatory information is contained within the DNA sequences of cis-regulatory elements and the epigenetic features of the chromatin surrounding these elements. Recent investigations in yeast, fly, and mammalian systems have made significant contributions toward our understanding of the relationship between gene activation and chromatin architecture at transcriptional promoters, but much work remains to improve our knowledge of this relationship at human promoters and other transcriptional regulatory elements, such as enhancers. Here, we report that human promoters and enhancers are associated with distinct chromatin signatures that can be employed to predict these classes of regulatory elements in the human genome. Using a combination of chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) experiments, we generated high-resolution maps of the chromatin architecture along 30 Mbp of the human genome, located promoters and enhancers in these regions, and characterized the histone modification features of these regulatory elements. We found that active promoters are marked by tri-methylation of histone H3 lysine 4 (H3K4me3) at the transcriptional start site (TSS) and mono-methylation of this residue (H3K4me1) downstream and upstream of the TSS. In contrast, enhancers are marked by H3K4me1 but not H3K4me3. Both types of regulatory elements are also associated with nucleosome depletion and varying degrees of histone acetylation and H3K4me2. We developed computational prediction algorithms that employ the distinct chromatin signatures to identify new promoters and enhancers, predicting over 200 promoters and 400 enhancers within the 30 Mbp regions. This approach correctly predicted over 84% of the regulatory elements identified in an independent, unbiased study of transcription factor binding in the same regions. Our results suggest a histone code for distinct classes of transcriptional regulatory elements, offering insights into the functional relationships between chromatin modifications and regulatory activity in human cells and providing a new resource for the functional annotation of the human genome. Keywords: ChIP-chip

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Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells

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