2023-10-05 ニューヨーク大学 (NYU)
◆自閉症は高い遺伝性を持つ障害で、遺伝子の変異が複雑な脳活動と機能の変化にどのように影響を与えるかを理解するのが難しかったが、この研究はその一端を明らかにしました。
◆研究チームは、CHD8遺伝子の変異がゲノム規制、遺伝子発現、およびニューロンの機能に影響を及ぼす方法を包括的に解明し、これらの変異が自閉症に関与する他の遺伝子と関連していることを示しています。
<関連情報>
- https://www.nyu.edu/about/news-publications/news/2023/october/genome-organization-autism.html
- https://www.sciencedirect.com/science/article/pii/S0002929723003178?dgcid=author
自閉症関連遺伝子CHD8のヘテロ接合体欠失は、広範な遺伝子発現の変化とクロマチンコンパクションを通じてシナプス機能を障害する Heterozygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction
Xi Shi, Congyi Lu, Alba Corman, Alexandra Nikish, Yang Zhou, Randy J. Platt, Ivan Iossifov, Feng Zhang, Jen Q. Pan, Neville E. Sanjana
The American Journal of Human Genetics Published: October 5, 2023
DOI:https://doi.org/10.1016/j.ajhg.2023.09.004
Summary
Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons. We identified hundreds of genes with altered expression, including many involved in neural development and excitatory synaptic transmission. Field recordings and single-cell electrophysiology revealed a 3-fold decrease in firing rates and synaptic activity in CHD8+/- neurons, as well as a similar firing-rate deficit in primary cortical neurons from Chd8+/- mice. These alterations in neuron and synapse function can be reversed by CHD8 overexpression. Moreover, CHD8+/- neurons displayed a large increase in open chromatin across the genome, where the greatest change in compaction was near autism susceptibility candidate 2 (AUTS2), which encodes a transcriptional regulator implicated in ASD. Genes with changes in chromatin accessibility and expression in CHD8+/- neurons have significant overlap with genes mutated in probands for ASD, intellectual disability, and schizophrenia but not with genes mutated in healthy controls or other disease cohorts. Overall, this study characterizes key molecular alterations in genome structure and expression in CHD8+/- neurons and links these changes to impaired neuronal and synaptic function.
