近日，美国哈佛医学院Katia Georgopoulos等研究人员合作发现，IKAROS在多个尺度上组装特定谱系的三维基因组结构。这一研究成果于2023年11月22日在线发表在《细胞》期刊上。

研究人员在B细胞前体中进行的功能缺失研究表明，IKAROS在为淋巴细胞发育做准备的过程中组装了跨越百万碱基距离的相互作用。来自IKAROS结合的增强子相互作用超越了CTCF强加的界限，从而在较小的不变拓扑结构域的骨干上建立起特定于谱系的调控单元。上皮细胞的功能增益证实了IKAROS在多个尺度上重构染色质结构的能力。虽然基因组编辑所需的Igκ基因座的压实是IKAROS在淋巴细胞中独有的功能，但其更普遍的功能是预配置基因组，进而支持特定谱系的基因表达，并抑制谱系外基因的激活，这为谱系限制提供了一个范例。

据介绍，由黏连蛋白和CTCF相互作用产生的染色质组织的一般水平足以限制调控元件之间的杂乱相互作用，但要配置基因组以引导基因表达变化，从而推动忠实的谱系进展，则需要超越这些限制的谱系特异性染色质组装。

附：英文原文

Title: Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS

Author: Yeguang Hu, Daniela Salgado Figueroa, Zhihong Zhang, Margaret Veselits, Sourya Bhattacharyya, Mariko Kashiwagi, Marcus R. Clark, Bruce A. Morgan, Ferhat Ay, Katia Georgopoulos

Issue&Volume: 2023/11/22

Abstract: A generic level of chromatin organization generated by the interplay between cohesinand CTCF suffices to limit promiscuous interactions between regulatory elements, buta lineage-specific chromatin assembly that supersedes these constraints is requiredto configure the genome to guide gene expression changes that drive faithful lineageprogression. Loss-of-function approaches in B cell precursors show that IKAROS assemblesinteractions across megabase distances in preparation for lymphoid development. Interactionsemanating from IKAROS-bound enhancers override CTCF-imposed boundaries to assemblelineage-specific regulatory units built on a backbone of smaller invariant topologicaldomains. Gain of function in epithelial cells confirms IKAROS’ ability to reconfigurechromatin architecture at multiple scales. Although the compaction of the Igκ locus required for genome editing represents a function of IKAROS unique to lymphocytes,the more general function to preconfigure the genome to support lineage-specific geneexpression and suppress activation of extra-lineage genes provides a paradigm forlineage restriction.

DOI: 10.1016/j.cell.2023.10.023

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01174-1