Large-Scale Discovery of Enhancers from Human Heart Tissue
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE32587 | GEO | 2011/12/04
SECONDARY ACCESSION(S): PRJNA147085
REPOSITORIES: GEO
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Project description: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
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Project description:Analysis of the transcriptional changes in the heart resulting from the loss of cardiac enhancers. As there remains a limited understanding of the phenotypic consequences of enhancer mutations, we examined the impact of loss of function mutations by deleting two enhancers near heart disease genes in mice. In both cases, we observed loss of target gene expression, as well as cardiac phenotypes consistent with heart disease in humans, highlighting the functional importance of enhancers for normal heart function, as well as the potential contribution of enhancer mutations to heart disease. Hearts were dissected from wild-type and enhancer-null mice (either embryonic or adult) and processed for deep RNA-seq analysis.
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Project description:Accurate control of tissue-specific gene expression plays a pivotal role in heart development. However, few cardiac transcriptional enhancers have thus far been identified. Extreme non-coding sequence conservation successfully predicts enhancers active in many tissues, but fails to identify substantial numbers of enhancers active in the heart. We used ChIP-seq with the enhancer-associated protein p300 from mouse embryonic heart tissue to identify over three thousand candidate heart enhancers genome-wide. In contrast to other studied tissues at this time-point, most candidate heart enhancers are not deeply conserved in vertebrate evolution. Nevertheless, the testing of 130 candidate regions in a transgenic mouse assay revealed that most of them reproducibly function as enhancers active in the heart, irrespective of their degree of evolutionary constraint. These results provide evidence for tissue-dependent differences in evolutionary constraint of enhancers acting through the transcriptional co-activator p300 at this time-point, and identify a large population of poorly conserved heart enhancers. Examination of p300 binding in embryonic stage 11.5 mouse heart and midbrain
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Project description:Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the genome-wide regulatory landscape in heart disease has remained obscure. Here we show that pervasive epigenomic changes occur in heart disease, with thousands of regulatory sequences reacquiring fetal-like chromatin signatures. We used RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from 18 healthy controls and 18 individuals with idiopathic dilated cardiomyopathy (DCM). Healthy individuals had a highly reproducible epigenomic landscape, consisting of more than 31,000 predicted heart enhancers. In contrast, we observed reproducible disease-associated gains or losses of activity at more than 7,500 predicted heart enhancers. Next, we profiled human fetal heart tissue by ChIP-seq and RNA-seq. Comparison with adult tissues revealed that the heart disease epigenome and transcriptome both shift toward a fetal-like state, with more than 3,400 individual enhancers sharing fetal regulatory properties. Our results demonstrate widespread epigenomic changes in DCM, and we provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of heart disease etiology.
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Project description:Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the genome-wide regulatory landscape in heart disease has remained obscure. Here we show that pervasive epigenomic changes occur in heart disease, with thousands of regulatory sequences reacquiring fetal-like chromatin signatures. We used RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from 18 healthy controls and 18 individuals with idiopathic dilated cardiomyopathy (DCM). Healthy individuals had a highly reproducible epigenomic landscape, consisting of more than 31,000 predicted heart enhancers. In contrast, we observed reproducible disease-associated gains or losses of activity at more than 7,500 predicted heart enhancers. Next, we profiled human fetal heart tissue by ChIP-seq and RNA-seq. Comparison with adult tissues revealed that the heart disease epigenome and transcriptome both shift toward a fetal-like state, with more than 3,400 individual enhancers sharing fetal regulatory properties. Our results demonstrate widespread epigenomic changes in DCM, and we provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of heart disease etiology.
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