Nde1 is required for heterochromatin compaction and stability in neocortical neurons.
Nde1 is required for heterochromatin compaction and stability in neocortical neurons.
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Nde1 是新皮质神经元异染色质压缩和稳定性所必需的
DOI：
10.1016/j.isci.2022.104354
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发表时间：
2022-06-17
期刊：
影响因子：
5.8
通讯作者：
Feng, Yuanyi
中科院分区：
文献类型：
--
作者：
Chomiak, Alison A.;Guo, Yan;Kopsidas, Caroline A.;McDaniel, Dennis P.;Lowe, Clara C.;Pan, Hongna;Zhou, Xiaoming;Zhou, Qiong;Doughty, Martin L.;Feng, Yuanyi
NDE1基因编码一种对大脑发育至关重要的支架蛋白。虽然双等位基因NDE1功能丧失(LOF)会导致小头畸形并严重的智力低下，但NDE1错义突变和拷贝数变异与多种神经精神疾病相关。然而，NDE1异常导致的不同表型的病因仍然难以捉摸。在这里，我们证明NDE1通过促进H4K20三甲基化介导的异染色质紧致来控制神经发生。这一机制形成了不同的染色质景观，并稳定了新皮质神经元的结构性异染色质。我们证明了NDE1可以进行动态的液-液相分离，分配到原子核，并与着丝粒和着丝粒卫星重复序列相互作用。NDE1 LOF导致核结构异常和DNA双链断裂，以及新皮质神经元着丝粒周围卫星重复序列的不稳定和去抑制。这些发现揭示了NDE1/NDE1在建立和保护神经元异染色质方面的关键作用。他们认为，异染色质的不稳定性会导致大范围的脑功能障碍。皮质神经发生与以H4K20me3为标志的异染色质紧密结合经历液-液相分离并与异染色质相互作用NDE1突变在神经前体分化过程中损害H4K20me3缺乏NDE1的神经元抑制异染色质并失去核和基因组完整性生物科学；分子生物学；神经科学
The NDE1 gene encodes a scaffold protein essential for brain development. Although biallelic NDE1 loss of function (LOF) causes microcephaly with profound mental retardation, NDE1 missense mutations and copy number variations are associated with multiple neuropsychiatric disorders. However, the etiology of the diverse phenotypes resulting from NDE1 aberrations remains elusive. Here we demonstrate Nde1 controls neurogenesis through facilitating H4K20 trimethylation-mediated heterochromatin compaction. This mechanism patterns diverse chromatin landscapes and stabilizes constitutive heterochromatin of neocortical neurons. We demonstrate that NDE1 can undergo dynamic liquid-liquid phase separation, partitioning to the nucleus and interacting with pericentromeric and centromeric satellite repeats. Nde1 LOF results in nuclear architecture aberrations and DNA double-strand breaks, as well as instability and derepression of pericentromeric satellite repeats in neocortical neurons. These findings uncover a pivotal role of NDE1/Nde1 in establishing and protecting neuronal heterochromatin. They suggest that heterochromatin instability predisposes a wide range of brain dysfunction. Cortical neurogenesis is coupled with heterochromatin compaction marked by H4K20me3 Nde1 undergoes liquid-liquid phase separation and interacts with heterochromatin Nde1 mutations impair H4K20me3 during neural progenitor differentiation Neurons lacking Nde1 derepress heterochromatin and lose nuclear and genomic integrity Biological sciences; Molecular biology; Neuroscience
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DOI：
10.4161/cc.20919
发表时间：
2012-07-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Gatti M;Pinato S;Maspero E;Soffientini P;Polo S;Penengo L
通讯作者：
Penengo L
影响因子：
56.9
作者：
Hoyt, Savannah J.;Storer, Jessica M.;Hartley, Gabrielle A.;Grady, Patrick G. S.;Gershman, Ariel;de Lima, Leonardo G.;Limouse, Charles;Halabian, Reza;Wojenski, Luke;Rodriguez, Matias;Altemose, Nicolas;Rhie, Arang;Core, Leighton J.;Gerton, Jennifer L.;Makalowski, Wojciech;Olson, Daniel;Rosen, Jeb;Smit, Arian F. A.;Straight, Aaron F.;Vollger, Mitchell R.;Wheeler, Travis J.;Schatz, Michael C.;Eichler, Evan E.;Phillippy, Adam M.;Timp, Winston;Miga, Karen H.;O'Neill, Rachel J.
通讯作者：
O'Neill, Rachel J.
影响因子：
11
作者：
通讯作者：
--
影响因子：
2.2
作者：
Guven, Ayse;Gunduz, Aysegul;Tolun, Ashhan
通讯作者：
Tolun, Ashhan
影响因子：
14.8
作者：
Bromberg, Kenneth D.;Mitchell, Taylor R. H.;Pappano, William N.
通讯作者：
Pappano, William N.