Neuronal activity modifies the chromatin accessibility landscape in the adult brain

Su, Yijing; Shin, Jaehoon; Zhong, Chun; Wang, Sabrina; Roychowdhury, Prith; Lim, Jongseuk; Kim, David; Ming, Guo Li; Song, Hongjun

doi:10.1038/nn.4494

Cited by 223 publications

(268 citation statements)

References 58 publications

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“…We found that learning increases chromatin accessibility genome-wide, supporting previous findings that neuronal activation increases chromatin accessibility (35). Our results, however, provide a genome-wide map of chromatin remodeling in response to behavior.…”

Section: Discussionsupporting

confidence: 90%

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

et al. 2018

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Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions—most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.

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Section: Discussionsupporting

confidence: 90%

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

et al. 2018

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“…For gene expression analysis, the total RNA fraction was immediately isolated from cultured mouse neural progenitor samples with RNeasy Mini Kit (Qiagen), treated with DNaseI and reverse-transcribed into the first-strand cDNA with SuperScript III (Thermo Fisher Scientific) (Su et al, 2017). cDNAs were used for SYBR-green based quantitative real-time PCR to measure the expression level of target genes with the comparative CT method (ABI) (Su et al, 2017).…”

Section: Star Methodsmentioning

confidence: 99%

“…cDNAs were used for SYBR-green based quantitative real-time PCR to measure the expression level of target genes with the comparative CT method (ABI) (Su et al, 2017). The primers used for quantitative PCR are listed in Table S1.…”

Section: Star Methodsmentioning

confidence: 99%

Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

et al. 2017

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SUMMARY Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells, and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.

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“…Detailed analysis of the chromatin accessibility in neurons with differential regenerative capacities will therefore be instrumental in engineering and developing new strategies to direct axon regeneration. Indeed, recent technical developments now enable researchers to study transcription and chromatin accessibility in a cell-type-specific manner 157 and have been applied to show that neuronal activity modifies the chromatin accessibility landscape in the adult brain 158 .…”

Section: Transcriptional Changesmentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

2018

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Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

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Neuronal activity modifies the chromatin accessibility landscape in the adult brain

Cited by 223 publications

References 58 publications

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

Intrinsic mechanisms of neuronal axon regeneration

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