A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart

被引：41

作者：

Iyer, Lavanya M. ^{[1
,2
]}

Nagarajan, Sankari ^{[3
,4
]}

Woelfer, Monique ^{[1
,2
]}

Schoger, Eric ^{[1
,2
]}

Khadjeh, Sara ^{[2
,5
]}

Zafiriou, Maria Patapia ^{[1
,2
]}

Kari, Vijayalakshmi ^{[3
]}

Herting, Jonas ^{[2
,5
]}

Pang, Sze Ting ^{[1
,2
]}

Weber, Tobias ^{[1
,2
]}

Rathjens, Franziska S. ^{[1
,2
]}

Fischer, Thomas H. ^{[2
,5
]}

Toischer, Karl ^{[2
,5
]}

Hasenfuss, Gerd ^{[2
,5
]}

Noack, Claudia ^{[1
,2
]}

Johnsen, Steven A. ^{[3
]}

Zelarayan, Laura C. ^{[1
,2
]}

机构：

[1] Georg August Univ, Univ Med Ctr Goettingen, Inst Pharmacol & Toxicol, D-37075 Gottingen, Germany

[2] German Ctr Cardiovasc Res DZHK Partner Site Goett, D-37075 Gottingen, Germany

[3] Georg August Univ, Clin Gen Visceral & Pediat Surg, Univ Med Ctr Goettingen, D-37075 Gottingen, Germany

[4] Canc Res UK CRUK CI, Cambridge CB2 0RE, England

[5] Georg August Univ, Univ Med Ctr Goettingen, Dept Cardiol & Pneumol, D-37075 Gottingen, Germany

来源：

NUCLEIC ACIDS RESEARCH | 2018年 / 46卷 / 06期

关键词：

TRANSCRIPTION; TARGET; ENHANCERS; PATHWAY; DIFFERENTIATION; PROLIFERATION; HYPERTROPHY; MECHANISMS; EXPRESSION; PATTERN;

D O I：

10.1093/nar/gky049

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p) Ser675-beta-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-beta-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of beta-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2-5 and GATA4 in stabilized-beta-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/beta-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing beta-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/beta-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway.

引用

页码：2850 / 2867

页数：18