Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation

ABSTRACT Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) alters splicing of DPF2, a subunit of BAF chromatin remodeling complexes. Dpf2 exon 7 is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 splicing, resulting in a longer DPF2-L isoform. Gene expression changes are induced by DPF2-L in ESC, and by DPF2-S in neurons. In ESC, chromatin immunoprecipitation locates DPF2-S but not DPF2-L at sites bound by pluripotency transcription factors. In neuronal progenitors, DPF2-S sites coincide with NFI protein binding, and DPF2-L sites with CTCF. DPF2-S sites show enhancer chromatin modifications, while DPF2-L sites show modifications associated with promoters. In sum, alternative splicing events during neuronal development impact chromatin organization by altering BAF complex targeting.