Unknown,Transcriptomics,Genomics,Proteomics

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Large-Scale Discovery of Enhancers from Human Heart Tissue

ABSTRACT: Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. While large numbers of heart enhancers have been identified using the mouse as a model system, many of these regulatory sequences are poorly conserved in the human genome. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ~6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, function and disease. To further validate their in vivo enhancer activity, we tested 65 of these human sequences in a transgenic mouse enhancer assay and observed that 43 (66%) drove reproducible reporter gene expression in the heart. These results support the discovery of a genome-wide set of non-coding sequences highly enriched in human heart enhancers which is likely to facilitate down-stream studies of the role of enhancers in development and pathological conditions of the heart. Examination of AcCBP/p300 binding in human adult heart, human fetal (16wk) heart and mouse postnatal day 2 heart

ORGANISM(S): Mus musculus

SUBMITTER: Matthew Blow

PROVIDER: E-GEOD-32587 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Large-scale discovery of enhancers from human heart tissue.

May Dalit D Blow Matthew J MJ Kaplan Tommy T McCulley David J DJ Jensen Brian C BC Akiyama Jennifer A JA Holt Amy A Plajzer-Frick Ingrid I Shoukry Malak M Wright Crystal C Afzal Veena V Simpson Paul C PC Rubin Edward M EM Black Brian L BL Bristow James J Pennacchio Len A LA Visel Axel A

Nature genetics 20111204 1

Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ∼6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, funct ...[more]

PMID: 22138689

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Project description:While the majority of protein-coding genes in the human genome have been identified, the location of the regulatory sequences that control their expression in time and space remains poorly defined. The importance of identifying these elements is underscored by a growing number of studies (such as GWAS) supporting a relationship between variation in non-coding sequences and human disease. M-BM- emonstrated that ChIP-Seq with p300 directly on human or mouse tissues represents a powerful method to identify the location and tissue-specific activity pattern of enhancers in the genome.M-BM- a highly specific chromatin mark for the prediction of in vivo enhancers, it is not without limitations. M-BM- comparison of p300-bound regions with previously generated enhancer sets shows that the majority of enhancers are activated independently of p300. To attempt to identify a larger proportion of enhancers in vivo, we have focused on several additional transcriptional coactivators that are hypothesized to be associated with active tissue-specific enhancers. M-BM- limited availability of ChIP-seq grade antibodies for these coactivators, FLAG-tag knock-in mice were generated and ChIP-seq using a FLAG antibody was performed on various tissues from e11.5 mouse embryos. Indeed, as these mouse lines have become available we have validated their valuable role as marks for transcriptional enhancers in vivo.M-BM- studies are expected to further expand the catalogue of in vivo functional enhancers, which will aid in the decoding of the regulatory genome and provide new insights into the role of gene regulation in human biology and disease. In addition to FLAG data, this accession includes histone acetylation / methylation ChIP-seq data from e11.5 mouse embryonic tissues. Histone ChIP-seq data was used in combination with FLAG data for various computational analyses. Examination of FLAG-labeled transcriptional coactivator binding in mouse embryonic stage 11.5 and embryonic stem cells

Dataset Information

Large-Scale Discovery of Enhancers from Human Heart Tissue

Publications

Large-scale discovery of enhancers from human heart tissue.

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