Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genome Res. 2022 Sep 27;32(9):1642-1654. doi: 10.1101/gr.276591.122.
Epigenetic regulation plays a critical role in many neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). In particular, many such disorders are the result of mutations in genes that encode chromatin-modifying proteins. However, although these disorders share many features, it is unclear whether they also share gene expression disruptions resulting from the aberrant regulation of chromatin. We examined five chromatin modifiers that are all linked to ASD despite their different roles in regulating chromatin. Specifically, we depleted ASH1L, CHD8, CREBBP, EHMT1, and NSD1 in parallel in a highly controlled neuronal culture system. We then identified sets of shared genes, or transcriptional signatures, that are differentially expressed following loss of multiple ASD-linked chromatin modifiers. We examined the functions of genes within the transcriptional signatures and found an enrichment in many neurotransmitter transport genes and activity-dependent genes. In addition, these genes are enriched for specific chromatin features such as bivalent domains that allow for highly dynamic regulation of gene expression. The down-regulated transcriptional signature is also observed within multiple mouse models of NDDs that result in ASD, but not those only associated with intellectual disability. Finally, the down-regulated transcriptional signature can distinguish between control and idiopathic ASD patient iPSC-derived neurons as well as postmortem tissue, demonstrating that this gene set is relevant to the human disorder. This work identifies a transcriptional signature that is found within many neurodevelopmental syndromes, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in ASD.
表观遗传调控在许多神经发育障碍 (NDDs) 中起着关键作用，包括自闭症谱系障碍 (ASD)。特别是，许多此类疾病是编码染色质修饰蛋白的基因突变的结果。然而，尽管这些疾病有许多共同特征，但尚不清楚它们是否也存在由于染色质异常调节而导致的基因表达紊乱。我们研究了五个与 ASD 相关的染色质修饰物，尽管它们在调节染色质方面的作用不同。具体来说，我们在一个高度受控的神经元培养系统中平行耗尽了 ASH1L、CHD8、CREBBP、EHMT1 和 NSD1。然后，我们确定了一组共享基因，或转录特征，这些基因在多个与 ASD 相关的染色质修饰物缺失后表达差异。我们研究了转录特征内基因的功能，发现许多神经递质转运基因和活性依赖性基因富集。此外，这些基因富集了特定的染色质特征，如允许基因表达高度动态调节的双价结构域。下调的转录特征也在导致 ASD 的多种 NDD 小鼠模型中观察到，但不在仅与智力障碍相关的模型中观察到。最后，下调的转录特征可以区分对照和特发性 ASD 患者 iPSC 衍生神经元以及死后组织，表明该基因集与人类疾病相关。这项工作确定了一个在许多神经发育综合征中都存在的转录特征，有助于阐明表观遗传调控与导致 ASD 的潜在细胞机制之间的联系。
