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

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dc.contributor.author Pei, Jiayi
dc.contributor.author Harakalova, Magdalena
dc.contributor.author Treibel, Thomas A.
dc.contributor.author Lumbers, R. Thomas
dc.contributor.author Boukens, Bastiaan J.
dc.contributor.author Efimov, Igor R.
dc.contributor.author Van Dinter, Jip T.
dc.contributor.author González, Arantxa
dc.contributor.author López, Begoña
dc.contributor.author El Azzouzi, Hamid
dc.contributor.author Van Den Dungen, Noortje
dc.contributor.author Van Dijk, Christian G.M.
dc.contributor.author Krebber, Merle M.
dc.contributor.author Den Ruijter, Hester M.
dc.contributor.author Pasterkamp, Gerard
dc.contributor.author Duncker, Dirk J.
dc.contributor.author Nieuwenhuis, Edward E.S.
dc.contributor.author De Weger, Roel
dc.contributor.author Huibers, Manon M.
dc.contributor.author Vink, Aryan
dc.contributor.author Moore, Jason H.
dc.contributor.author Moon, James C.
dc.contributor.author Verhaar, Marianne C.
dc.contributor.author Kararigas, Georgios
dc.contributor.author Mokry, Michal
dc.contributor.author Asselbergs, Folkert W.
dc.contributor.author Cheng, Caroline
dc.date.accessioned 2022-08-26T01:04:15Z
dc.date.available 2022-08-26T01:04:15Z
dc.date.issued 2020-07-14
dc.identifier.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
dc.identifier.issn 1868-7075
dc.identifier.other PURE: 43313198
dc.identifier.other PURE UUID: 27fd7ecd-b8dc-4b9e-842a-18d80e7048ea
dc.identifier.other Scopus: 85088043650
dc.identifier.uri https://hdl.handle.net/20.500.11815/3372
dc.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).
dc.description.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.
dc.language.iso en
dc.relation.ispartofseries Clinical Epigenetics; 12(1)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Histone acetylation
dc.subject Myocardial remodeling
dc.subject Transcription factor
dc.subject Transcriptome
dc.subject Molecular Biology
dc.subject Genetics
dc.subject Developmental Biology
dc.subject Genetics (clinical)
dc.title H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 32664951
dc.identifier.doi https://doi.org/10.1186/s13148-020-00895-5
dc.relation.url http://www.scopus.com/inward/record.url?scp=85088043650&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine

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