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.
journal_name
Cell Resjournal_title
Cell researchauthors
Gao R,Liang X,Cheedipudi S,Cordero J,Jiang X,Zhang Q,Caputo L,Günther S,Kuenne C,Ren Y,Bhattacharya S,Yuan X,Barreto G,Chen Y,Braun T,Evans SM,Sun Y,Dobreva Gdoi
10.1038/s41422-019-0168-1subject
Has Abstractpub_date
2019-06-01 00:00:00pages
486-501issue
6eissn
1001-0602issn
1748-7838pii
10.1038/s41422-019-0168-1journal_volume
29pub_type
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