Soma-to-germline transformation in chromatin-linked neurodevelopmental disorders?
Soma-to-germline transformation in chromatin-linked neurodevelopmental disorders?
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DOI：
10.1111/febs.16196
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Iwase S
中科院分区：
文献类型：
--
作者：
Bonefas KM;Iwase S
许多染色质调节因子的突变导致神经发育障碍（NDD），其机制尚不清楚。可以理解的是，大多数研究都集中在染色质调节因子如何控制与大脑发育和功能直接相关的基因表达，如突触基因。然而，令人惊讶的是，一些NDD模型显示了生殖系基因在大脑中的异位表达。这些生殖系基因通常仅在原始生殖细胞、睾丸和卵巢中表达，用于生殖细胞发育和有性生殖。已在几种NDD中报道了这种异位生殖系基因表达，包括免疫缺陷、着丝粒不稳定性、面部异常综合征1、Kleefstra综合征1、Rett综合征、MeCP 2复制综合征和精神发育迟滞、X连锁综合征、Claes詹森型。负责基因DNMT 3B、G9 A/GLP、MECP 2和KDM 5C都编码用于基因沉默的染色质调节因子。因此，这些突变可能导致生殖系基因去抑制，进而导致脑细胞严重的身份危机-可能干扰正常的大脑发育。因此，生殖系基因的异位表达是定义该NDD子集的独特标志，并进一步暗示了生殖系基因沉默在脑发育过程中的重要性。然而，生殖系基因表达对大脑发育的功能影响仍未确定。这篇透视文章探讨了这种明显的体细胞到种系的转化是如何产生的，以及它是如何通过基因组不稳定和受损的感觉纤毛形成来干扰神经发育的。此外，我们还讨论了如何测试这些假设的实验，以最终确定异位生殖系成绩单染色质连接的NDD的贡献。染色质是我们基因组的3D结构，由包裹在组蛋白周围的DNA组成。许多染色质调节因子的突变导致神经发育障碍（NDD），但我们不知道为什么。我们发现NDD的一个子集在大脑中表现出生殖系基因抑制的丧失，但它们的影响尚不清楚。这些有害的精子和卵子基因在发育过程中的异位表达可能会损害大脑的发育和功能。
Mutations in numerous chromatin regulators cause neurodevelopmental disorders (NDDs) with unknown mechanisms. Understandably, most research has focused on how chromatin regulators control gene expression that is directly relevant to brain development and function, such as synaptic genes. However, some NDD models surprisingly show ectopic expression of germline genes in the brain. These germline genes are usually expressed only in the primordial germ cells, testis, and ovaries for germ-cell development and sexual reproduction. Such ectopic germline gene expression has been reported in several NDDs, including Immunodeficiency, Centromere instability, Facial anomalies syndrome 1, Kleefstra syndrome 1, Rett syndrome, MeCP2 duplication syndrome, and Mental Retardation, X-linked Syndromic, Claes Jensen Type. The responsible genes, DNMT3B, G9A/GLP, MECP2, and KDM5C, all encode chromatin regulators for gene silencing. These mutations may therefore lead to germline gene derepression, and in turn, a severe identity crisis of brain cells — potentially interfering with normal brain development. Thus, the ectopic expression of germline genes is a unique hallmark defining this NDD subset and further implicates the importance of germline gene silencing during brain development. The functional impact of germline gene expression on brain development, however, remains undetermined. This perspective article explores how this apparent soma-to-germline transformation arises and how it may interfere with neurodevelopment through genomic instability and impaired sensory cilia formation. Furthermore, we also discuss how to test these hypotheses experimentally to ultimately determine the contribution of ectopic germline transcripts to chromatin-linked NDDs. Chromatin is the 3D structure of our genome and consists of DNA wrapped around histone proteins. Mutations in numerous chromatin regulators cause neurodevelopmental disorders (NDDs) yet we do not know why. We found a subset of NDDs show loss germline gene suppression in the brain however their impact is unknown. Ectopic expression of these deleterious sperm and egg genes during development may impair brain development and function.
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DOI：
10.1126/science.aba5960
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Delgado RN;Mansky B;Ahanger SH;Lu C;Andersen RE;Dou Y;Alvarez-Buylla A;Lim DA
通讯作者：
Lim DA
影响因子：
3.5
作者：
Ben-Shachar S;Chahrour M;Thaller C;Shaw CA;Zoghbi HY
通讯作者：
Zoghbi HY
DOI：
10.1002/ajmg.1320400411
发表时间：
1991-09-15
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
ENGEL, E;DELOZIERBLANCHET, CD
通讯作者：
DELOZIERBLANCHET, CD
影响因子：
8.8
作者：
Belalcazar HM;Hendricks EL;Zamurrad S;Liebl FLW;Secombe J
通讯作者：
Secombe J
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V