In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity.

Autor:	Cao Y; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Zhang X; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Akerberg BN; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Yuan H; Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou, China (H.Y.)., Sakamoto T; Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.S., D.P.K.)., Xiao F; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., VanDusen NJ; Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (N.J.V.)., Zhou P; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Sweat ME; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Wang Y; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Prondzynski M; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Chen J; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Zhang Y; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Wang P; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.)., Kelly DP; Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.S., D.P.K.)., Pu WT; Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).; Harvard Stem Cell Institute, Cambridge, MA (W.T.P.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2023 Mar 14; Vol. 147 (11), pp. 881-896. Date of Electronic Publication: 2023 Jan 27.
DOI:	10.1161/CIRCULATIONAHA.122.061955
Abstrakt:	Background: Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined. Methods: We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes. Results: We identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs. Conclusions: We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.
Databáze:	MEDLINE
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