NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.
NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.
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DOI：
10.1016/j.molcel.2021.09.020
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发表时间：
2021-11-18
期刊：
影响因子：
16
通讯作者：
Reinberg D
中科院分区：
文献类型：
--
作者：
Liu S;Aldinger KA;Cheng CV;Kiyama T;Dave M;McNamara HK;Zhao W;Stafford JM;Descostes N;Lee P;Caraffi SG;Ivanovski I;Errichiello E;Zweier C;Zuffardi O;Schneider M;Papavasiliou AS;Perry MS;Humberson J;Cho MT;Weber A;Swale A;Badea TC;Mao CA;Garavelli L;Dobyns WB;Reinberg D
包括多梳抑制复合体1(PRC1)的异质复合体家族有助于建立抑制转录的兼性异染色质。然而，已知的两个PRC1物种ncPRC1.3和ncPRC1.5包含新的成分AUTS2、P300和CK2，它们将这种抑制功能转化为转录激活功能。在这里，我们报告了AUTS2 HX重复区域突变的患者表现出AUTS2和P300相互作用的缺陷，以及反映Rubinstein-Taybi综合征的发育障碍，这主要与CREBBP/EP300杂合致病变异有关。此外，AUTS2的缺失或其HX重复结构域的突变会导致发育基因子集的错误调节，并阻碍小鼠胚胎干细胞的运动神经元分化。值得注意的是，转录因子核呼吸因子1(NRF1)在这个神经发育过程中显示出一个新的和不可或缺的作用，是ncPRC1.3重新招募到染色质所必需的。刘等人。报道称，患者来源的AUTS2 HX重复序列突变破坏了AUTS2与P300的相互作用，从而阻碍了AUTS2-ncPRC1.3介导的激活转录。这种突变反映了P300中与RSTS相关的那些突变。此外，NRF1介导的AUTS2募集对AUTS2-ncPRC1.3靶点的激活和脑发育至关重要。
The heterogeneous family of complexes comprising Polycomb Repressive Complex 1 (PRC1) is instrumental to establishing facultative heterochromatin that is repressive to transcription. Yet, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2 that convert this repressive function to that of transcription activation. Here, we report that patients harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to a mis-regulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. Notably, the transcription factor, Nuclear Respiratory Factor 1 (NRF1) exhibits a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin. Liu et al. report that patient-derived mutations in the HX repeat of AUTS2 disrupt its interaction with P300, thereby thwarting AUTS2-ncPRC1.3-mediated active transcription. Such mutations reflect those in P300 proper with respect to RSTS. Moreover, NRF1-mediated AUTS2 recruitment is paramount to the activation of AUTS2-ncPRC1.3 targets and brain development.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
64.8
作者：
Bannister, AJ;Kouzarides, T
通讯作者：
Kouzarides, T
DOI：
10.1126/science.1191078
发表时间：
2010-10-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bonasio R;Tu S;Reinberg D
通讯作者：
Reinberg D
影响因子：
4
作者：
Beunders, Gea;van de Kamp, Jiddeke;Sistermans, Erik A.
通讯作者：
Sistermans, Erik A.
影响因子：
7.7
作者：
Briggs, James Alexander;Li, Victor C.;Krischner, Marc W.
通讯作者：
Krischner, Marc W.