Function and modulation of genomic cardiomyopathy enhancers

This project investigates cardiomyocyte enhancer-dependent molecular circuits of heart disease, with a focus on enhancers bound by the key cardiac transcription factor GATA4. We will use CRISPR-mediated epigenetic perturbation to dissect the functional contribution of cardiomyocyte enhancers and to modulate pathophysiological processes in vitro and in vivo. Furthermore, will we decode the impact of sequence context and TF-cooperativity on enhancer activity to identify the mechanistic basis of non-coding genetic risk factors.

This CRC project enabled the development of an efficient AAV-based method for CRISPRi-mediated epigenetic silencing of regulatory elements in cardiac myocytes in vivo and in vitro. This functional epigenetic approach offers a novel and efficient method for modulating gene expression in the heart and could become a standard approach for modeling cardiovascular disease and translational research.

This project enabled us to functionally test and resolve the spatial genome organization of cis-regulatory elements and genetic variants in atrial, ventricular, and failing human cardiomyocytes and linked them to heart disease traits, including heart failure and QT syndrome.

SELECTED SCIENTIFIC OUTCOMES

2014

"Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease"

Gilsbach R*, Preissl S*, Gruning BA, Schnick T, Burger L, Benes V, Wurch A, Bonisch U, Gunther S, Backofen R, Fleischmann BK, Schubeler D & Hein L.

Nat Commun. 5:5288, 2014

2015

"Deciphering the Epigenetic Code of Cardiac Myocyte Transcription"

Preissl S, Schwaderer M, Raulf A, Hesse M, Gruning BA, Kobele C, Backofen R, Fleischmann BK, Hein L & Gilsbach R.

Circ Res. 117:413-23, 2015.

2018

"Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo"

Gilsbach R, Schwaderer M, Preissl S, Gruning BA, Kranzhofer D, Schneider P, Nuhrenberg TG, Mulero-Navarro S, Weichenhan D, Braun C, Dressen M, Jacobs AR, Lahm H, Doenst T, Backofen R, Krane M, Gelb BD & Hein L.

Nat Commun. 9:391, 2018.

2017

"DNA methylation signatures follow preformed chromatin compartments in cardiac myocytes"

Nothjunge S, Nuhrenberg TG, Gruning BA, Doppler SA, Preissl S, Schwaderer M, Rommel C, Krane M, Hein L & Gilsbach R.

Nat Commun. 8:1667, 2017

2024

"In Vivo Silencing of Regulatory Elements Using a Single AAV-CRISPRi Vector"

Laurette P, Cao C, Ramanujam D, Schwaderer M, Lueneburg T, Kuss S, Weiss L, Dilshat R, Furlong EEM, Rezende F, Engelhardt S & Gilsbach R.

Circ Res. 134:223-5, 2024.

2026

"Chamber-Specific Chromatin Architecture Guides Functional Interpretation of Disease-Associated Cis-Regulatory Elements in Human Cardiomyocytes"

Haydar S, Bednarz R, Laurette P, Sobitov I, Diaz i Pedrosa N, Videm P, Lüneburg T, Kuss S, Lahm H, Dressen M, Krane M, Schmidt C, Grüning BA, Voigt N, Streckfuss-Boemeke K & Gilsbach R.

Nature Commun. Nat Commun 17, 117, 2026

2026

"Cardiac Epigenome in Heart Development and Disease."

Laurette P & Gilsbach R.

Nature Reviews Cardiology. 2026

involved in the project

Prof. Dr.

Ralf Gilsbach

A02

Other scientific staff involved in the project

Shaza Haydar
Patrick Laurette
Cecilie Fang Ying Zhang
Arda Ceylan

A02

Summary

SELECTED SCIENTIFIC OUTCOMES

involved in the project

Other scientific staff involved in the project