Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2024-12-16 , DOI: 10.1038/s41594-024-01431-2 Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren
|
While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.
中文翻译:

小鼠胚胎组织中 3D 基因组和表观基因组的综合分析
虽然最近根据染色质可及性和组蛋白修饰模式注释了一组涉及小鼠胎儿发育的丰富推定顺式调节序列,但描述它们在发育调节基因表达中的作用仍然具有挑战性。为了填补这一空白,我们在这里绘制了 7 个小鼠胎儿组织和前脑六个发育阶段基因组中基因启动子和远端序列之间的染色质接触。我们确定了以 14,138 个蛋白质编码基因为中心的 248,620 个长程染色质相互作用,并表征了它们的组织间变异和发育动力学。对来自相同组织的先前表观基因组和转录组数据集的交互组进行综合分析,揭示了染色质接触与远端增强子的染色质状态以及预测靶基因的基因表达模式之间的强相关性。我们预测了 15,098 个候选增强子的靶基因,并使用它们来注释人类基因组中隐藏着人类疾病风险变异的同源候选增强子的靶基因。我们提供的证据表明,精神分裂症和其他成人疾病风险变异经常在胎儿增强子中发现,为成人疾病的胎儿起源假说提供了支持。