Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain.
Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain.
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DOI：
10.1186/s13072-022-00471-6
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发表时间：
2022-12-03
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
--
作者：
智力残疾是唐氏综合征（Down Syndrome，DS）的一个众所周知的标志，其由人类21号染色体（human chromosome 21，HSA 21）的关键区域的三倍化引起。近年来进行了大量研究，以了解单个三重基因对DS相关脑病理学的贡献。全球转录组的改变和广泛的变化，在建立神经谱系，以及他们的分化和功能成熟，建议在三体全基因组染色质组织的改变。高迁移率族核小体结合结构域1（HMGN 1），由HSA 21表达，是一种染色质重塑蛋白，其促进染色质解压缩并且与组蛋白H3（H3 K27 ac）上的乙酰化赖氨酸27相关，组蛋白H3是与活性转录相关的标记。最近的研究表明，HMGN 1在三体中的过度表达与DS相关的B细胞急性淋巴细胞白血病（B-ALL）的发生有关。HMGN 1已被证明拮抗Polycomb抑制复合物2（PRC 2）的活性，并阻止组蛋白H3赖氨酸27三甲基化标记（H3 K27 me 3）的沉积，这与转录抑制和基因沉默有关。然而，通过PRC 2靶基因对脑细胞病理学的去抑制而增加HMGN 1水平的可能后果尚未引起关注。本文就HMGN 1在脑发育中的功能意义进行了综述，并对PRC 2在神经系统发育中的重要作用进行了总结。对HMGN 1过表达如何导致DS中异常脑细胞表型的机制理解，如神经祖细胞增殖改变、皮质结构异常、髓鞘形成减少、神经变性和21三体中阿尔茨海默病相关病理学，将促进靶向染色质的DS治疗方法的发展。
Intellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), expressed from HSA21, is a chromatin remodeling protein that facilitates chromatin decompaction and is associated with acetylated lysine 27 on histone H3 (H3K27ac), a mark correlated with active transcription. Recent studies causatively linked overexpression of HMGN1 in trisomy and the development of DS-associated B cell acute lymphoblastic leukemia (B-ALL). HMGN1 has been shown to antagonize the activity of the Polycomb Repressive Complex 2 (PRC2) and prevent the deposition of histone H3 lysine 27 trimethylation mark (H3K27me3), which is associated with transcriptional repression and gene silencing. However, the possible ramifications of the increased levels of HMGN1 through the derepression of PRC2 target genes on brain cell pathology have not gained attention. In this review, we discuss the functional significance of HMGN1 in brain development and summarize accumulating reports about the essential role of PRC2 in the development of the neural system. Mechanistic understanding of how overexpression of HMGN1 may contribute to aberrant brain cell phenotypes in DS, such as altered proliferation of neural progenitors, abnormal cortical architecture, diminished myelination, neurodegeneration, and Alzheimer’s disease-related pathology in trisomy 21, will facilitate the development of DS therapeutic approaches targeting chromatin.
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影响因子：
64.8
作者：
Bannister, AJ;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
2.5
作者：
Belichenko, Pavel V.;Klescrevnikov, Alexander M.;Mobley, William C.
通讯作者：
Mobley, William C.
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE
影响因子：
3.9
作者：
BYVOET, P;SHEPHERD, GR;HARDIN, JM
通讯作者：
HARDIN, JM
影响因子：
3.5
作者：
Rodríguez-Ortiz A;Montoya-Villegas JC;García-Vallejo F;Mina-Paz Y
通讯作者：
Mina-Paz Y