Abstract
SWI/SNF or BAF chromatin-remodeling complexes are polymorphic assemblies of homologous subunit families that remodel nucleosomes and facilitate tissue-specific gene regulation during development. BAF57/SMARCE1 is a BAF complex subunit encoded in animals by a single gene and is a component of all mammalian BAF complexes. In vivo, the loss of SMARCE1 would lead to the formation of deficient combinations of the complex which might present limited remodeling activities. To address the specific contribution of SMARCE1 to the function of the BAF complex, we generated CRISPR/Cas9 mutations of smarce1 in zebrafish. Smarce1 mutants showed visible defects at 72 hpf, including smaller eyes, abnormal body curvature and heart abnormalities. Gene expression analysis revealed that the mutant embryos displayed defects in endocardial development since early stages, which led to the formation of a misshapen heart tube. The severe morphological and functional cardiac problems observed at 4 dpf were correlated with the substantially increased expression of different cardiac transcription factors. Additionally, we showed that Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for the recruitment of the BAF complex to these regions.
Highlights
The SWItch/Sucrose Non-Fermentable (SWI/SNF) complexes are ATP-dependent chromatin remodeling machines that are evolutionarily conserved from yeast to humans
Mammalian BAF complexes are further subdivided into BAF and PBAF (Polybromo-associated BAF) complexes: BAF complexes are defined by the AT Rich Interactive Domain 1 (ARID) containing subunits ARID1A or ARID1B, while PBAF complexes include BAF200 as the ARID-containing subunit
It has been shown that mutations in SMARCE1 predispose to meningioma disease[15,16] and to the Coffin-Siris syndrome[17], and this gene has been connected to malignancy
Summary
The SWItch/Sucrose Non-Fermentable (SWI/SNF) complexes are ATP-dependent chromatin remodeling machines that are evolutionarily conserved from yeast to humans. Their enzymatic function involves remodeling nucleosomal DNA, thereby facilitating the binding of transcriptional factors to nucleosomal templates[1]. At least 28 genes encode subunits of the SWI/SNF complex. SWI/SNF complexes (often referred to as BAF) can form various assemblies from homologous subunits. The central catalytic activity of the BAF complex is ATP hydrolysis This activity is achieved by the Brahma (BRM/SMARCA2) or Brahma-Related Gene 1 (BRG1/SMARCA4) subunits. Repression of neuronal genes in non-neuronal cells, SMARCE1 interacts with the transcriptional co-repressor Co-REST and facilitates repression[14]. It has been shown that mutations in SMARCE1 predispose to meningioma disease[15,16] and to the Coffin-Siris syndrome[17], and this gene has been connected to malignancy
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