Ding Bo, Liu Ying, Liu Zhiheng, Zheng Lina, Xu Ping, Chen Zhao, Wu Peiyao, Zhao Ying, Pan Qian, Guo Yu, Wei Wensheng, Wang Wei
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0359, USA.
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
Sci Adv. 2021 Nov 5;7(45):eabi6020. doi: 10.1126/sciadv.abi6020. Epub 2021 Nov 3.
Most noncoding regions of the human genome do not harbor any annotated element and are even not marked with any epigenomic or protein binding signal. However, an overlooked aspect of their possible role in stabilizing 3D chromatin organization has not been extensively studied. To illuminate their structural importance, we started with the noncoding regions forming many 3D contacts (referred to as hubs) and performed a CRISPR library screening to identify dozens of hubs essential for cell viability. Hi-C and single-cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and affect the expressions of distal genes. This study revealed the 3D structural importance of noncoding loci that are not associated with any functional element, providing a previously unknown mechanistic understanding of disease-associated genetic variations (GVs). Furthermore, our analyses also suggest a possible approach to develop therapeutics targeting disease-specific noncoding regions that are critical for disease cell survival.
人类基因组的大多数非编码区域没有任何注释元件，甚至没有任何表观基因组或蛋白质结合信号标记。然而，它们在稳定三维染色质组织中可能发挥的作用这一被忽视的方面尚未得到广泛研究。为了阐明它们的结构重要性，我们从形成许多三维接触的非编码区域（称为枢纽）入手，进行了CRISPR文库筛选，以鉴定数十个对细胞活力至关重要的枢纽。高通量染色体构象捕获技术（Hi-C）和单细胞转录组分析表明，删除这些区域会显著改变染色质组织，并影响远端基因的表达。这项研究揭示了与任何功能元件无关的非编码位点的三维结构重要性，为疾病相关遗传变异提供了前所未有的机制理解。此外，我们的分析还提出了一种可能的方法，来开发针对对疾病细胞存活至关重要的疾病特异性非编码区域的疗法。
