Volume 29, No 6, Jun 2019
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 29 Issue 6, June 2019: 486-501 | Open Access
ORIGINAL ARTICLES
Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
Rui Gao 1,2,3 , Xingqun Liang4 , Sirisha Cheedipudi1 , Julio Cordero 1,2,3 , Xue Jiang4 , Qingquan Zhang 4 , Luca Caputo 1, Stefan Günther1 ,Carsten Kuenne1 , Yonggang Ren 1,2,3 , Shoumo Bhattacharya5 , Xuejun Yuan1 , Guillermo Barreto 1 , Yihan Chen 4 , Thomas Braun1 , Sylvia M. Evans6 , Yunfu Sun4 and Gergana Dobreva 1,2,3,7
1 Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; 2Department of Anatomy and Developmental Biology, CBTM, Medical Faculty Mannheim, Heidelberg
University, Mannheim, Germany; 3European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; 4Key Laboratory of
Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; 5Department of Cardiovascular Medicine, University of Oxford,Oxford, UK; 6Department of Medicine, Skaggs School of Pharmacy, University of California, San Diego, La Jolla, CA 92093, USA and 7Medical Faculty, University of Frankfurt, 60590
Frankfurt am Main, Germany
Correspondence: Sylvia M. Evans (syevans@ucsd.edu) or Yunfu Sun (yfsun@tongji.edu.cn) or Gergana Dobreva (Gergana.Dobreva@medma.uni-heidelberg.de)(Gergana.Dobreva@mpi-bn.mpg.de)These authors contributed equally: Rui Gao, Xingqun Liang, Sirisha Cheedipudi and Julio Co
Generation of widely differing and specialized cell types from a single totipotent zygote involves large-scale transcriptional changes and chromatin reorganization. Pioneer transcription factors play key roles in programming the epigenome and facilitating recruitment of additional regulatory factors during successive cell lineage specification and differentiation steps. Here we show that Isl1 acts as a pioneer factor driving cardiomyocyte lineage commitment by shaping the chromatin landscape of cardiac progenitor cells. Using an Isl1 hypomorphic mouse line which shows congenital heart defects, genome-wide profiling of Isl1 binding together with RNA- and ATAC-sequencing of cardiac progenitor cells and their derivatives, we uncover a regulatory network downstream of Isl1 that orchestrates cardiogenesis. Mechanistically, we show that Isl1 binds to compacted chromatin and works in concert with the Brg1-Baf60c-based SWI/SNF complex to promote permissive cardiac lineage-specific alterations in the chromatin landscape not only of genes with critical functions in cardiac progenitor cells, but also of cardiomyocyte structural genes that are highly expressed when Isl1 itself is no longer present. Thus, the Isl1/Brg1-Baf60c complex plays a crucial role in orchestrating proper cardiogenesis and in establishing epigenetic memory of cardiomyocyte fate commitment.
https://doi.org/10.1038/s41422-019-0168-1
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