Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0359, USA.
Bioinformatics and Systems Biology program, University of California, San Diego, La Jolla, CA 92093-0359, USA.
Nucleic Acids Res. 2024 Aug 27;52(15):8778-8799. doi: 10.1093/nar/gkae535.
Non-coding regions of the human genome are important for functional regulations, but their mechanisms remain elusive. We used machine learning to guide a CRISPR screening on hubs (i.e. non-coding loci forming many 3D contacts) and significantly increased the discovery rate of hubs essential for cell growth. We found no clear genetic or epigenetic differences between essential and nonessential hubs, but we observed that some neighboring hubs in the linear genome have distinct spatial contacts and opposite effects on cell growth. One such pair in an epigenetically quiescent region showed different impacts on gene expression, chromatin accessibility and chromatin organization. We also found that deleting the essential hub altered the genetic network activity and increased the entropy of chromatin accessibility, more severe than that caused by deletion of the nonessential hub, suggesting that they are critical for maintaining an ordered chromatin structure. Our study reveals new insights into the system-level roles of non-coding regions in the human genome.
人类基因组的非编码区域对于功能调控非常重要，但它们的作用机制仍不清楚。我们使用机器学习指导 CRISPR 筛选枢纽（即形成许多 3D 接触的非编码基因座），显著提高了发现对细胞生长至关重要的枢纽的发现率。我们没有发现必需和非必需枢纽之间有明显的遗传或表观遗传差异，但我们观察到线性基因组中的一些相邻枢纽具有不同的空间接触，并对细胞生长有相反的影响。在一个表观遗传静止区域中的这样一对枢纽表现出对基因表达、染色质可及性和染色质组织的不同影响。我们还发现，删除必需枢纽会改变遗传网络活性并增加染色质可及性的熵，比删除非必需枢纽造成的更为严重，这表明它们对于维持有序的染色质结构至关重要。我们的研究揭示了非编码区域在人类基因组中系统水平作用的新见解。
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