Kim Il Bin, Lee Taeyeop, Lee Junehawk, Kim Jonghun, Lee Suho, Koh In Gyeong, Kim Jae Hyun, An Joon-Yong, Lee Hyunseong, Kim Woo Kyeong, Ju Young Seok, Cho Yongseong, Yu Seok Jong, Kim Soon Ae, Oh Miae, Han Dong Wook, Kim Eunjoon, Choi Jung Kyoon, Yoo Hee Jeong, Lee Jeong Ho
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
Department of Psychiatry, Hanyang University Guri Hospital, Guri, 11923, Republic of Korea.
Mol Psychiatry. 2022 Nov;27(11):4680-4694. doi: 10.1038/s41380-022-01697-2. Epub 2022 Jul 15.
Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD). We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions. Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development. Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.
三维染色质相互作用调节基因表达。对于自闭症谱系障碍（ASD），染色质相互作用中新生突变（DNM）的意义仍知之甚少。我们从242个韩国单基因家庭中生成了813个全基因组序列以检测DNM，并确定了在染色质相互作用中可能受非编码DNM影响的靶基因。染色质相互作用中的非编码DNM显著参与了与ASD风险相关的转录失调。相应地，靶基因在发育中的大脑中表现出与ASD相关的时空表达，并在与ASD相关的生物学途径（如组蛋白修饰）中富集。关于ASD的临床特征，染色质相互作用中的非编码DNM尤其导致ASD先证者的智商水平较低。我们使用两个复制队列，即西蒙斯单基因队列（SSC）和MSSNG，进一步验证了我们的发现，并表明ASD先证者中存在非编码DNM破坏的染色质相互作用的一致富集。在两个ASD家庭中生成人类诱导多能干细胞后，我们能够证明染色质相互作用中的非编码DNM在早期神经发育阶段改变了靶基因的表达。综上所述，我们的发现表明，ASD先证者中的非编码DNM通过染色质相互作用导致与ASD风险相关的早期神经发育破坏。
