ISWI remodeler facilitates cBAF genomic binding to drive cell fate transition

Abstract The ISWI chromatin remodeler regulates nucleosome spacing using one of two ATPase subunits Snf2h (Smarca5) and Snf2l (Smarca1). While Snf2h stable knockout (KO) is known to markedly reduce genomic binding of CTCF, an architectural protein organizing the 3D genome, ISWI’s role in regulating genomic binding and function of lineage-determining transcription factors (LDTFs) during cell fate transition remains largely unclear. Using conditional KO mice and derived cells, we show Snf2h and Snf2l are partially redundant and are required for embryonic development of muscle and adipose tissue as well as myogenesis and adipogenesis in culture. Stable KO of ISWI impairs LDTF-stimulated cell differentiation and disrupts de novo binding of the myogenic LDTF MyoD and the cBAF chromatin remodeler. Surprisingly, acute depletion of ISWI leaves de novo MyoD binding landscape largely intact while disrupting MyoD-dependent recruitment of cBAF and CTCF, with minimal effects on constitutive genomic binding of cBAF and CTCF. Together, our findings identify ISWI as an important mediator connecting LDTF binding to cBAF recruitment and chromatin organization during cell fate transition. Bullet points - ISWI ATPases Snf2h and Snf2l are partially redundant and essential for muscle and adipose development - ISWI is required for MyoD, C/EBPα, and PPARγ-driven cell fate transition - Stable KO of ISWI disrupts genomic binding of MyoD, while acute depletion does not - Acute ISWI deletion disrupts MyoD-dependent, but not constitutive, genomic binding of cBAF and CTCF