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Genome-wide fetalization of enhancer architecture in heart disease [ChIP-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126571 | GEO | 2019/04/02

REPOSITORIES: GEO

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Genome-wide fetalization of enhancer architecture in heart disease [RNA-Seq]

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.

2019-04-02 | GSE126569 | GEO

Large-Scale Discovery of Enhancers from Human Heart Tissue

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Defining the fetal gene program at single cell resolution in dilated cardiomyopathy.

Project description:It is hypothesized that the postnatal heart adopts a fetal-like transcriptional state in response to cardiac stress. Here, we analyse the transcriptome of 74,451 nuclei from fetal, non-diseased and early-onset DCM samples, which revealed 7 broad cell clusters across fetal, ND and DCM samples. We find that there are no statistically significant shifts in cellular composition between DCM and ND hearts. Also, pseudo-bulk profiling revealed that transcriptional pathways perturbed in DCM are predominantly associated with cardiomyocytes, fibroblasts and immune cells. We advance the hypothesis that only a small subset (<10%) of fetal genes is re-engaged in both cardiomyocyte and cardiac fibroblast of DCM. This study provides a framework to identify critical gene expression networks that underpin disease pathogenesis independent of genetic aetiology.

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Genome-wide chromatin state in non-failing and dilated cardiomyaphty human left ventricles [PLAC-seq]

Project description:We conducted chromatin immunoprecipitation followed by sequencing (ChIP-seq) and proximity ligation-assisted ChIP-seq (PLAC-seq) for enhancers and promoters (E-P) using left ventricular tissues from dilated cardiomyopathy (DCM) patients and non-heart failure (NF) donors. Differential active enhancer H3K27ac and promoter H3K4me3 regions were identified between NF and DCM. While the average read density (ARD) for H3K27ac is similar between NF and DCM, the ARD of H3K4me3 is significantly lower in DCM samples than in NF.Super-enhancer (SE) analysis revealed that 929 and 129 genes linked to NF- and DCM-specific SE, respectively, and three unique SE-associated genes between NF and DCM were identified.Moreover, the differential E-P interactions were observed in the known heart failure gene loci and are correlated with the gene expression levels. Motif analysis identified known cardiac factors and possible novel players for DCM. We have established cistrome of four histone modifications and long-range chromatin interaction for enhancers and promoters in NF and DCM tissues. The differential histone modifications and E-P interactions were found in DCM, and these differences were associated with the gene expression level of a subset of disease-associated genes in human heart failure.

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Genome-wide chromatin state in non-failing and dilated cardiomyaphty human left ventricles [ChIP-Seq]

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2021-10-01 | GSE154096 | GEO

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Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

Project description:About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2 KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, NPPA. The median survival of CAP2 CKO mice was 98 days, while CCG-1423-8u treated CKO mice survived for 116 days and also maintain normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.

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