An insulator that regulates chromatin extrusion and class switch recombination.
An insulator that regulates chromatin extrusion and class switch recombination.
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调节染色质挤出和类别转换重组的绝缘体。
DOI：
10.1073/pnas.2026399118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Yu,Kefei
中科院分区：
文献类型：
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作者：
Yu,Kefei
在PNAS中，Zhang et al. (1)报告发现了CTCF结合元件（CBE）簇的绝缘子功能，该元件簇定义了免疫球蛋白（IG）重（H）链基因座的3′-边界并调节IgH类别转换重组（CSR）（图1）。这项研究不仅解决了CSR中这些CBE功能相关性的不确定性（2，3），而且进一步加强了同一研究者在范式转换研究中提出的“粘附介导的染色质环挤出”模型（4-6）。CSR环挤出模型假设了一个由Sμ、突触供体开关（S）区和一组位于IgH基因座3′端的增强子组成的“重组中心”。在这个约200 kb的环中，凝聚介导的染色质挤出负责将转录激活的受体开关区域募集到重组中心，以参与CSR（5）。该模型具有广泛适用的含义-超出抗原受体基因重排（V（D）J重组和CSR）的范围-因为它可能适用于许多涉及长程染色质动力学的生物过程。CSR由B细胞特异性酶激活诱导的胞苷脱氨酶（AID）启动，并受到涉及多个转录增强子、启动子和CBE的复杂调控。[鼓励读者阅读Oudinet等人的优秀评论。(7)以及其中的参考文献]。本研究（1）中研究的区域（3′ IgH CBE）位于广泛研究的28-kb调控区（3′ IgHRR）下游，该调控区含有4个转录增强子（最初被鉴定为DNA酶I超敏位点，hs 1至hs 4）。3′ IgHRR被广泛认为是跨越200-kb IgH恒定区基因座的转录活性的主要调节因子，并且是“重组中心”的主要组分。虽然3′ IgHRR在促进开关区转录和CSR中的重要作用已被确定，但3′ IgH CBE（也含有HS位点：hs 5至hs 8）的功能尚不清楚。以前的研究评估了
In PNAS, Zhang et al.(1) report the discovery of the insulator function of a cluster of CTCF-binding elements (CBEs) that defines the 3′-boundary of the immunoglobulin (Ig) heavy (H) chain locus and regulates IgH class switch recombination (CSR)(Fig. 1). This study not only resolves uncertainties surrounding the functional relevance of these CBEs in CSR (2, 3) but further strengthens a “cohesion-mediated chromatin loop extrusion” model put forth in paradigm-shifting studies from the same investigators (4–6). The CSR loop extrusion model postulates a “recombination center” composed minimally of Sμ, the synapsed donor switch (S) region, and a group of enhancers located at the 3′ end of the IgH locus. Cohesionmediated chromatin extrusion within this∼ 200-kb loop is responsible for recruiting a transcriptionactivated acceptor switch region into the recombination center to participate in CSR (5). This model has broadly applicable implications—beyond the realm of antigen receptor gene rearrangements (both V (D) J recombination and CSR)—as it is likely applicable to many biological processes that involve long-range chromatin dynamics.CSR is initiated by the B cell-specific enzyme activation-induced cytidine deaminase (AID), and is under complex regulation involving multiple transcription enhancers, promoters, and CBEs.[Readers are encouraged to see an excellent review by Oudinet et al.(7) and the references therein.] The region under investigation (3′ IgH CBEs) in the current study (1) is present downstream of an extensively studied 28-kb regulatory region (3′ IgHRR) that contains four transcription enhancers (initially identified as DNase I hypersensitive sites, hs1 to hs4). The 3′ IgHRR is widely considered as the master regulator of transcriptional activities across the∼ 200-kb IgH constant region locus and is a major component of the “recombination center.” While the essential role of 3′ IgHRR in promoting switch region transcription and CSR has been firmly established, the function of the 3′ IgH CBEs (also containing HS sites: hs5 to hs8) has been less clear. Previous studies that assessed the