The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus

Abstract

Fetal alcohol spectrum disorders are a leading cause of intellectual disability worldwide. Previous studies have shown that developmental ethanol exposure results in loss of microRNAs (miRNAs) including miR-9, and loss of these miRNAs, in turn, mediates some of ethanol’s teratogenic effects in the developing brain. We previously found that ethanol increased methylation at the miR-9-2 encoding gene locus in mouse fetal neural stem cells (NSC), advancing a mechanism for epigenetic silencing of this locus and consequently, miR-9 loss in NSCs. Therefore, we assessed the role of the BAF (BRG1/BRM-Associated Factor) complex, which disassembles nucleosomes to facilitate access to chromatin, as an epigenetic mediator of ethanol’s effects on miR-9. Chromatin immunoprecipitation and DNAse-I hypersensitivity analyses showed that the BAF-complex was associated with both transcriptionally accessible and heterochromatic regions of the miR-9-2 locus, and that disintegration of the BAF-complex by combined knockdown of BAF170 and BAF155 resulted in a significant decrease in miR-9. We hypothesized that ethanol exposure would result in loss of BAF-complex function at the miR-9-2 locus. However, ethanol exposure significantly increased mRNA transcripts for maturation-associated BAF complex members, BAF170, SS18, ARID2, BAF60a, BRM/BAF190b and BAF53b. Ethanol also significantly increased BAF-complex binding within an intron containing a CpG island and in the terminal exon encoding precursor (pre)-miR-9-2. These data suggest that the BAF complex may adaptively respond to ethanol exposure to protect against a complete loss of miR-9-2 in fetal NSCs. Chromatin remodeling factors may adapt to the presence of a teratogen, to maintain transcription of critical miRNA regulatory pathways.

The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders

“…Recently Mathies et al (2017) identified several SNP clusters within BAF-genes that correlate with alcohol use disorder in humans, including Baf47 , Baf60a , and Crest [ 141 ]. Lastly, ethanol exposure during neuronal development induces expression of Baf53b , Baf57 , Baf60 , Baf200 , and Crest [ 142 ]. While these studies demonstrate that drugs of abuse are capable of altering nBAF, they fail to establish a mechanistic link between nBAF-mediated CRC function and long-lasting drug-associated behavior.…”

Binge‐like ethanol drinking activates anaplastic lymphoma kinase signaling and increases the expression of STAT3 target genes in the mouse hippocampus and prefrontal cortex

“…A study in Caenorhabditis elegans found that most of the SWI/SNF genes (12 out of 13) were required for either initial sensitivity to ethanol or for acute functional recovery from ethanol exposure, 82 highlighting the connection between ethanol and the SWI/SNF complex. In vitro studies have also found ethanol‐induced changes in gene expression or DNA methylation of SWI/SNF complex genes 83,84 . Finally, a transcriptomic study of mouse hippocampus after chronic intermittent ethanol vapor exposure found increased expression of several Smarc genes, including Smarce1 , Smarca4 and Smarcc1 85 .…”

Epigenetic mediators and consequences of excessive alcohol consumption

“…miR-9 expression is decreased in neural stem cells after ethanol exposure, and miR-9 knockdown mimics the effects of ethanol on craniofacial development in a zebrafish model (Pappalardo-Carter et al, 2013; Sathyan, Golden, & Miranda, 2007). Burrowes et al (this issue) provide evidence that developmental chromatin remodeling, due to the maturation of the BAF (Brg/brm-associated factors) complex, can be adaptive and protective in response to ethanol exposure and act to preserve miR-9 expression. Prenatal alcohol exposure can also affect histone post-translational modifications in a dose-dependent manner in embryonic stem cells (Veazey et al, this issue).…”