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The BAF chromatin remodeling complex regulates gene expression programs essential for mammalian neural crest development

ABSTRACT: Neural crest cells (NCCs) are a multipotent cell population that contributes to the development of many tissues including craniofacial, pharyngeal arch arteries, and cardiac outflow tract (OFT). The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role BAF complex, we deleted BAF155 and BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in NCCs. Mouse embryos lacking BAF155/170 in NCCs displayed early lethality due to a wide range of developmental defects including craniofacial defects, pharyngeal arch artery defects, and OFT defects. We observed reduced proliferation, increased cell death, and impaired migration of cardiac NCCs to the OFT in BAF155/170 mutants. RNAseq analysis on sorted NCCs revealed that the BAF complex regulates the expression of numerous genes essential for neural crest development. We observed downregulation of Hippo and Notch signaling pathways, both essential for the migration, proliferation, and differentiation of the NCCs. The BAF complex interacts with transcription factors to modulate the transcriptional program. Therefore, we performed transcription factor enrichment analysis on the RNAseq data set and identified several transcription factors including Hey1, Hey2, and Hes5 that may directly or indirectly interact with the BAF complex in NCCs. We also found that Brg1 interact with Tead transcription factors and the interaction was impaired in BAF155/170 knockdown cells. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.

ORGANISM(S): Mus musculus

PROVIDER: GSE153121 | GEO | 2021/03/05

REPOSITORIES: GEO

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Project description:BAF155, as a component of a chromatin remodeling complex, is thought to be involved in the regulation of gene expression. Baf155 knockdown in ES cells results in misregulation of hundreds of genes (Ho et al., 2009). The Baf155msp3 allele presents a unique case for gene expression analysis wherein the BAF complex appears to be intact, in contrast to disruption of the BAF complex when BAF155 function is lost (Chen and Archer, 2005; Sohn et al., 2007). To examine gene expression in the Baf155msp3 mutant at the time of neural tube closure, we performed RNA-Seq and compared gene expression levels between homozygous wildtype and homozygous mutant embryos. After extensive analysis of the RNA-Seq data comparing all 3 mutants to all 3 WT replicates, 78 genes were identified as being upregulated on average in the mutant samples while 22 genes were downregulated. To facilitate an understanding of global gene expression differences, Ingenuity Pathway Analysis (IPA) was used to assign functional categories to the up- and down-regulated genes in the mutants. The most significant molecular and cellular functions of these genes were: 1. cellular movement (1.46E-04>p>4.12E-02), 2. cell death and survival (2.69E-04>p>4.12E-02), and 3. cell growth and proliferation (2.69E-04>p>3.41E-02). Many neuronal genes were significantly misregulated as well. Overall, the RNA-Seq analysis revealed that surprisingly few genes showed altered expression in Baf155 mutant neural tissue, given the broad epigenetic role of the BAF complex, but included genes involved in neural development and cell survival. Moreover, gene expression changes between individual mutants were variable even though the NTD was consistently observed. This suggests that inconsistent gene regulation contributes to failed neural tube closure. RNA was isolated from somite matched (21-23 somites) and phenotype matched cranial tissue of homozygous wildtype and homozygous mutant embryos (3 of each genotype) at E9.5 just after the time of neural tube closure. At E9.5, the vast majority of the embryonic neural tube is comprised of proliferating neural progenitor cells, constituting a relatively homogeneous cell population.

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The BAF chromatin remodeling complex regulates gene expression programs essential for mammalian neural crest development

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