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H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts

H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts


Title: H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts
Author: Pei, Jiayi
Harakalova, Magdalena
Treibel, Thomas A.
Lumbers, R. Thomas
Boukens, Bastiaan J.
Efimov, Igor R.
Van Dinter, Jip T.
González, Arantxa
López, Begoña
El Azzouzi, Hamid
... 17 more authors Show all authors
Date: 2020-07-14
Language: English
Scope:
Department: Faculty of Medicine
Series: Clinical Epigenetics; 12(1)
ISSN: 1868-7075
DOI: https://doi.org/10.1186/s13148-020-00895-5
Subject: Histone acetylation; Myocardial remodeling; Transcription factor; Transcriptome; Molecular Biology; Genetics; Developmental Biology; Genetics (clinical)
URI: https://hdl.handle.net/20.500.11815/3372

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Citation:

Pei , J , Harakalova , M , Treibel , T A , Lumbers , R T , Boukens , B J , Efimov , I R , Van Dinter , J T , González , A , López , B , El Azzouzi , H , Van Den Dungen , N , Van Dijk , C G M , Krebber , M M , Den Ruijter , H M , Pasterkamp , G , Duncker , D J , Nieuwenhuis , E E S , De Weger , R , Huibers , M M , Vink , A , Moore , J H , Moon , J C , Verhaar , M C , Kararigas , G , Mokry , M , Asselbergs , F W & Cheng , C 2020 , ' H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts ' , Clinical Epigenetics , vol. 12 , no. 1 , 106 . https://doi.org/10.1186/s13148-020-00895-5

Abstract:

Background: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. Results: We detected chromatin regions with differential acetylation activity (DARs; P adj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. Conclusions: Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology.

Description:

This work was supported by the Netherlands Foundation for Cardiovascular Excellence (to C.C.), the NWO VENI grant (no. 016.176.136 to M.H.), two NWO VIDI grants (no. 91714302 to C.C. and no. 016096359 to M.C.V), the Erasmus MC fellowship grant (to C.C.), the RM fellowship grant of the UMC Utrecht (to C.C.), Wilhelmina Children’s Hospital research funding (no. OZF/14 to M.H.), the Netherlands Cardiovascular Research Initiative: An initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS: to J.P., M.H., F.W.A., and CVON2014-11 RECONNECT: to C.C., M.C.V., G.P., M.M., D.D.), and the Dutch Heart Foundation (Queen of Heart: to C.C., H.D.R., M.C.V, G.P.), UCL Hospitals NIHR Biomedical Research Centre (to F.W.A.), the doctoral research fellowships by the National Institute of Health Research (NIHR; DRF-2013-06-102 to T.A.T.), and National Institutes of Health (USA) grant LM010098 (to J.H.M.). Publisher Copyright: © 2020 The Author(s).

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