The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory

Ciernia, Annie Vogel; Matheos, Dina P.; Barrett, Ruth M.; Kramar, Enikoe A.; Azzawi, Soraya; Chen, Yuncai; Magnan, Christophe; Zeller, Michael; Sylvain, A.; Häettig, Jakob; Jia, Yousheng; Tran, Anthony; Dang, Richard; Post, Rebecca J.; Chabrier, Meredith A.; Babayan, Alex H.; Wu, Jiang; Crabtree, Robert H.; Baldi, Pierre; Baram, Tallie Z.; Lynch, Gary; Wood, Marcelo A.

doi:10.1038/nn.3359

Cited by 222 publications

(293 citation statements)

References 60 publications

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“…Notably, ACTL6B is a neuron-specific component of the SWI/SNF chromatin remodeling complex. 58 We also highlight a syn- LGD GDM are present at this locus, and we found no other NS GDMs associated with ASD risk in the proband. Taken together, these new mosaic calls provide additional support for high-confidence ASD risk genes and highlight candidates as potential contributors to ASD risk.…”

supporting

confidence: 48%

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Krupp

Barnard

Duffourd

et al. 2017

Preprint

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Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted.

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supporting

confidence: 48%

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Krupp

Barnard

Duffourd

et al. 2017

Preprint

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“…SWI/SNF is important in the proper development of brain structures as well as in the function of differentiated neurons (42)(43)(44)(45), so we asked if there is a role for SWI/SNF in adults for AFT. We identified a requirement for SWI/SNF function in adult cells using a temperature-sensitive mutant allele of swsn-1.…”

Section: Discussionmentioning

confidence: 99%

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.SWI/SNF | alcohol | C. elegans | chromatin remodeling | GWAS

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“…The regulation of gene expression requires not only an activation of transcription factors but also the recruitment of multifunctional coactivators that are independently regulated and directly involved in the chromatin remodeling underlying epigenetic regulatory mechanisms (Rosenfeld and Glass 2001). For example, recent work demonstrated the importance of chromatin remodeling factors like the SWI/SNF complex in neuronal function underlying memory (Vogel-Ciernia et al 2013). While CBP's function as a platform to recruit other required coactivators appears to be indispensable for CREB-dependent transcription, the recruitment for lysine acetyltransferase activity is transcription unit specific and may depend on the structure of chromatin at a specific locus and/or a specific cell type (Puri et al 1997;Korzus et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Prefrontal consolidation supports the attainment of fear memory accuracy

et al. 2014

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The neural mechanisms underlying the attainment of fear memory accuracy for appropriate discriminative responses to aversive and nonaversive stimuli are unclear. Considerable evidence indicates that coactivator of transcription and histone acetyltransferase cAMP response element binding protein (CREB) binding protein (CBP) is critically required for normal neural function. CBP hypofunction leads to severe psychopathological symptoms in human and cognitive abnormalities in genetic mutant mice with severity dependent on the neural locus and developmental time of the gene inactivation. Here, we showed that an acute hypofunction of CBP in the medial prefrontal cortex (mPFC) results in a disruption of fear memory accuracy in mice. In addition, interruption of CREB function in the mPFC also leads to a deficit in auditory discrimination of fearful stimuli. While mice with deficient CBP/CREB signaling in the mPFC maintain normal responses to aversive stimuli, they exhibit abnormal responses to similar but nonrelevant stimuli when compared to control animals. These data indicate that improvement of fear memory accuracy involves mPFC-dependent suppression of fear responses to nonrelevant stimuli. Evidence from a context discriminatory task and a newly developed task that depends on the ability to distinguish discrete auditory cues indicated that CBP-dependent neural signaling within the mPFC circuitry is an important component of the mechanism for disambiguating the meaning of fear signals with two opposing values: aversive and nonaversive.

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The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory

Cited by 222 publications

References 60 publications

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Prefrontal consolidation supports the attainment of fear memory accuracy

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