Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes in late cortical development and beyond

Abstract

The multi-subunit BAF (SWI/SNF) complex is capable of using energy generated from ATP hydrolysis to reorder chromatin structure. Such chromatin changes are known to affect cell biological processes through gene expression regulation. Thus, BAF complex plays pivotal roles in many developmental event. As a focus of the studies present, we identified the BAF complex as a powerful regulator of coticogenesis and embryogenesis. In this study, we employed a novel mouse model system in which deletion of the BAF complex subunits BAF155 and BAF170 results in proteomic degradations of the entire BAF complex and resultant loss of its epigenetic function. The first part of the thesis, highlights how the BAF complex stability is dependent on the dual presence of the scaffolding subunits BAF155 and BAF170, and the disturbance in the H3K27me2/3 epigenetic landscape when they are ablated specifically in the forebrain under the control Foxg1-Cre activity or in the entire embryo using the ubiquitous-inducible CAG-Cre. Preliminary evidence of the involvement of BAF complex in cortical development was thus obtained in the first part of the studies. In the second part, we gathered conclusive evidence on how the BAF complex regulates cortical and hippocampal development. Our investigation in the dcKO_hGFAP_Cre developing cortex revealed the BAF complexes induces heterochromatin state at gene loci involved in neural progenitor proliferation and Wnt signaling; leading to their suppression. On the other hand, the BAF complex enhances the transcription of neuronal differentiation-related genes by promoting euchromatin formation at associated genomic regions. Together, we reported that the activity of the BAF complex ensures the appropriate proliferative capacity of neural progenitors and their neuronal output in late cortical development.