In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
Abstract:
Alteration of chromatin conformation has a profound effect on gene expression, and can lead to heart failure, which remains a major cause of death worldwide. ATP-dependent chromatin remodelers utilize the energy of ATP to remodel chromatin in specific regions of the genome. However, the mechanisms of ATP-dependent chromatin remodeling and how they connect to the genome remain poorly understood. We have discovered that the nucleosome remodeler Bromodomain PHD-finger Transcription Factor (BPTF), the largest subunit of the Nucleosome Remodeling Factor (NURF), plays an important role in cardiac hypertrophy. Our preliminary data show that BPTF is enriched in failing human hearts, a phenomenon similarly observed in mouse hearts subjected to pressure overload hypertrophy (TAC). BPTF is up-regulated in primary neonatal rat ventricular myocytes (NRVM) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) stimulated with the hypertrophic agonist phenylephrine (PE). Strikingly, specific silencing of BPTF in NRVM and hiPSC-CMs, inhibits the expression of the atrial natriuretic peptide (ANP), a marker of cardiac hypertrophy. Chromatin immunoprecipitation performed in NRVM show that BPTF binds to the ANP promoter, but not to GAPDH. Proteomics experiments performed in failing human hearts revealed a multi-protein complex formed between BPTF and novel chromatin regulators. At the level of the nucleosome, BPTF in combination with one of its partners, remodels chromatin by facilitating nucleosomes “sliding” along the DNA. This mechanism is mediated by the binding of BPTF to histone H3 trimethylated at Lysine-4 (H3K4me3), an “active” mark of transcription also up-regulated in the early phase of cardiac hypertrophy in NRVM and in mouse TAC hearts. Our study suggests a novel chromatin signature controlled by BPTF, that dictates specific gene patterns implicated in pathological cardiac hypertrophy. Our study uncovers a new epigenetic mechanism controlling pathological cardiac remodeling and heart failure.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.125.suppl_1.371
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
1467838-X
