SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.
SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.
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DOI：
10.1038/s41467-023-40992-6
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发表时间：
2023-09-25
影响因子：
16.6
通讯作者：
Blewitt, Marnie E.
中科院分区：
文献类型：
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作者：
Tapia del Fierro, Andres;den Hamer, Bianca;Benetti, Natalia;Jansz, Natasha;Chen, Kelan;Beck, Tamara;Vanyai, Hannah;Gurzau, Alexandra D.;Daxinger, Lucia;Xue, Shifeng;Ly, Thanh Thao Nguyen;Wanigasuriya, Iromi;Iminitoff, Megan;Breslin, Kelsey;Oey, Harald;Krom, Yvonne D.;van der Hoorn, Dinja;Bouwman, Linde F.;Johanson, Timothy M.;Ritchie, Matthew E.;Gouil, Quentin A.;Reversade, Bruno;Prin, Fabrice;Mohun, Timothy;van der Maarel, Silvere M.;Mcglinn, Edwina;Murphy, James M.;Keniry, Andrew;de Greef, Jessica C.;Blewitt, Marnie E.
3D染色质结构和基因沉默之间的相互作用还不完全清楚。在这里，我们报告了一个新的点突变的非经典SMC蛋白SMCHD1，增强其沉默能力在内源性发育目标。此外，它还导致在面肩肱型肌营养不良症相关的大卫星阵列D4Z4处增强的沉默，从而导致由该重复编码的DUX4的增强的抑制。增强的SMCHD1沉默干扰发育Hox基因激活，导致小鼠同源异型转化。奇怪的是，突变体SMCHD1似乎增强了对其他表观遗传调节因子（包括PRC2和CTCF）的绝缘，同时耗尽了与在SMCHD1不存在的情况下观察到的类似的长距离染色质相互作用。这些数据表明，SMCHD1在长距离染色质相互作用中的作用与基因沉默或隔离染色质没有直接联系，从而完善了SMCHD1介导的染色质调节的不同水平如何相互作用以在正常发育和疾病中引起基因沉默的模型。在这里，作者揭示了染色质蛋白SMCHD1中的新变体突变增强了SMCHD1介导的基因沉默，包括在FSHD疾病相关位点，同时耗尽了SMCHD1介导的染色质相互作用，表明这些SMCHD1功能是不相关的。
The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1’s role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease. Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.
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影响因子：
--
作者：
Yin, Danqing;Ritchie, Matthew E;Jabbari, Jafar S;Beck, Tamara;Blewitt, Marnie E;Keniry, Andrew
通讯作者：
Keniry, Andrew
影响因子：
3.7
作者：
Das S;Chadwick BP
通讯作者：
Chadwick BP
影响因子：
12.3
作者：
Daxinger L;Harten SK;Oey H;Epp T;Isbel L;Huang E;Whitelaw N;Apedaile A;Sorolla A;Yong J;Bharti V;Sutton J;Ashe A;Pang Z;Wallace N;Gerhardt DJ;Blewitt ME;Jeddeloh JA;Whitelaw E
通讯作者：
Whitelaw E
影响因子：
16.6
作者：
Benetti, Natalia;Gouil, Quentin;Tapia Del Fierro, Andres;Beck, Tamara;Breslin, Kelsey;Keniry, Andrew;McGlinn, Edwina;Blewitt, Marnie E
通讯作者：
Blewitt, Marnie E
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE