Gene by environment interaction mouse model reveals a functional role for 5-hydroxymethylcytosine in neurodevelopmental disorders.
Gene by environment interaction mouse model reveals a functional role for 5-hydroxymethylcytosine in neurodevelopmental disorders.
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DOI：
10.1101/gr.276137.121
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发表时间：
2022-03
期刊：
影响因子：
7
通讯作者：
Alisch RS
中科院分区：
文献类型：
--
作者：
Papale LA;Madrid A;Zhang Q;Chen K;Sak L;Keleş S;Alisch RS
敲除 Cntnap2 的小鼠表现出神经发育行为的改变、纹状体 GABA 信号传导的缺陷，以及与人类神经发育障碍有关的大量基因的直向同源物中环境敏感 DNA 甲基化修饰（5-羟甲基胞嘧啶 [5hmC]）的全基因组破坏。我们测试了承受产前应激的成年 Cntnap2 杂合小鼠（Cntnap2+/-；缺乏行为或神经病理异常），发现产前应激的 Cntnap2+/- 雌性小鼠表现出重复行为和社交能力改变，类似于纯合子表型。基因组分析揭示了海马和纹状体 5hmC 水平的破坏，这与这些表型相关基因（例如 Reln、Dst、Trio 和 Epha5）转录水平的改变有关。染色质免疫沉淀结合高通量测序和海马核裂解物下拉数据表明，5hmC 丰度改变了这些基因（例如 Palld、Gigyf1 和 Fry）启动子附近转录因子 CLOCK 的结合，为 5hmC 在基因调控中发挥了机制作用。这些数据共同支持了精神疾病起源的基因与环境假设，并提供了一种方法来识别导致复杂人类疾病的难以捉摸的因素。
Mouse knockouts of Cntnap2 show altered neurodevelopmental behavior, deficits in striatal GABAergic signaling, and a genome-wide disruption of an environmentally sensitive DNA methylation modification (5-hydroxymethylcytosine [5hmC]) in the orthologs of a significant number of genes implicated in human neurodevelopmental disorders. We tested adult Cntnap2 heterozygous mice (Cntnap2+/−; lacking behavioral or neuropathological abnormalities) subjected to a prenatal stress and found that prenatally stressed Cntnap2+/− female mice show repetitive behaviors and altered sociability, similar to the homozygote phenotype. Genomic profiling revealed disruptions in hippocampal and striatal 5hmC levels that are correlated to altered transcript levels of genes linked to these phenotypes (e.g., Reln, Dst, Trio, and Epha5). Chromatin immunoprecipitation coupled with high-throughput sequencing and hippocampal nuclear lysate pull-down data indicated that 5hmC abundance alters the binding of the transcription factor CLOCK near the promoters of these genes (e.g., Palld, Gigyf1, and Fry), providing a mechanistic role for 5hmC in gene regulation. Together, these data support gene-by-environment hypotheses for the origins of mental illness and provide a means to identify the elusive factors contributing to complex human diseases.
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DOI：
10.1016/j.jphysparis.2017.06.002
发表时间：
2016-11-01
期刊：
Journal of physiology, Paris
影响因子：
--
作者：
Geoffray, M-M;Nicolas, A;Georgieff, N
通讯作者：
Georgieff, N
影响因子：
4.8
作者：
Bronson, Stefanie L.;Bale, Tracy L.
通讯作者：
Bale, Tracy L.
影响因子：
7.7
作者：
Hu S;Wan J;Su Y;Song Q;Zeng Y;Nguyen HN;Shin J;Cox E;Rho HS;Woodard C;Xia S;Liu S;Lyu H;Ming GL;Wade H;Song H;Qian J;Zhu H
通讯作者：
Zhu H
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5
作者：
Ceschi, Grazia;Billieux, Joel;Van der Linden, Martial
通讯作者：
Van der Linden, Martial