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9 Publications visible to you, out of a total of 9
CRISPLD1: a novel conserved target in the transition to human heart failure.

Abstract (Expand)

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are … lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca(2+) cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca(2+) handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca(2+)-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca(2+) regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.

Authors: S. Khadjeh, V. Hindmarsh, F. Weber, L. Cyganek, R. O. Vidal, S. Torkieh, K. Streckfuss-Bomeke, D. Lbik, M. Tiburcy, B. A. Mohamed, S. Bonn, K. Toischer, G. Hasenfuss

Date Published: 7th Mar 2020

Publication Type: Journal Article

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

Abstract (Expand)

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.

Authors: L. M. Iyer, S. Nagarajan, M. Woelfer, E. Schoger, S. Khadjeh, M. P. Zafiriou, V. Kari, J. Herting, S. T. Pang, T. Weber, F. S. Rathjens, T. H. Fischer, K. Toischer, G. Hasenfuss, C. Noack, S. A. Johnsen, L. C. Zelarayan

Date Published: 6th Apr 2018

Publication Type: Journal Article

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