Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate

Rui Gao,Sirisha Cheedipudi,Xuejun Yuan,Qingquan Zhang,Shoumo Bhattacharya,Luca Caputo,Stefan Günther,Guillermo Barreto,Yunfu Sun,Gergana Dobreva,Xue Jiang,Carsten Kuenne,Sylvia M Evans,Thomas Braun,Yihan Chen,Yonggang Ren,Xingqun Liang,Julio Cordero

doi:10.1038/s41422-019-0168-1

Abstract

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.

Highlights

The differentiation of stem/progenitor cells into distinct lineages involves a coordinated series of large-scale transcriptional changes and chromatin reorganization
Isl[1] hypomorphic embryos show defects in cardiac morphogenesis, cardiomyocyte differentiation and maturation To investigate the mechanisms through which Isl[1] regulates cardiogenesis, we utilized an Isl[1] knockout mouse line, which shows early embryonic lethality[9,22] and an Isl[1] hypomorphic mouse line (Supplementary information, Fig. S1a–d),[23] which survives until birth, allowing us to analyze the role of Isl[1] in second heart field (SHF) structures that are dependent on Isl[1], as well as during later stages of embryonic heart development
Magnetic resonance imaging (MRI) and 3D reconstructions confirmed the presence of various cardiac outflow tract (OFT) abnormalities, ventricular septal defects (VSDs) and atrial septal defects (ASDs) (Fig. 1e, f)

Summary

Introduction

The differentiation of stem/progenitor cells into distinct lineages involves a coordinated series of large-scale transcriptional changes and chromatin reorganization. A special type of transcription factors, named pioneer transcription factors, engage developmentally silenced genes embedded in “closed” chromatin covered by nucleosomes.[1,2,3,4] Pioneer factor binding on its own is not sufficient for gene activation, but it imparts competence for transcription by chromatin opening. Chromatin opening facilitates subsequent recruitment of additional transcription factors and other regulatory proteins, which work in concert to induce a cell-type-specific gene expression program during the successive steps involved in lineage specification and differentiation.[1,2,3,4] During cardiogenesis, multiple transcription factors cooperate and are integrated in regulatory networks, which strictly control a transcriptional program that ensures proper heart development.[5,6,7,8]

Methods

Results

Conclusion