Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.
Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.
复制标题
DOI：
10.1371/journal.pone.0094968
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lachman HM
中科院分区：
文献类型：
--
作者：
Lin M;Zhao D;Hrabovsky A;Pedrosa E;Zheng D;Lachman HM
精神分裂症（SZ）和自闭症谱系障碍（ASD）是高度遗传的神经精神障碍，尽管环境因素，如母体免疫激活（MIA），也发挥了作用。在动物模型中，细胞因子介导MIA对神经发生和行为的影响。然而，MIA刺激剂也可以诱导发热反应，这可能通过热休克（HS）调节的细胞应激途径对神经发生产生独立影响。然而，这一点尚未得到充分研究。为了帮助理解发烧在MIA中的作用，我们使用了最近描述的人脑发育模型，其中诱导多能干细胞（iPSC）分化成类似于头三个月端脑的三维神经元聚集体。对在39°C下热激24小时的聚集体进行RNA-seq，连同保持在37°C下的它们的对照配偶体一起进行沿着。186个基因在HS后显示出显著的表达差异（p<0.05），包括已知的HS诱导基因，如预期的，以及编码NGFR和许多SZ和ASD候选者的那些基因，包括SMARCA 2、DPP 10、ARNT 2、AHI 1和ZNF 804 A。HS期间这些基因的表达减少或增加的程度与拷贝丢失和拷贝获得拷贝数变体（CNV）中发现的相似，尽管HS的影响可能是短暂的。对某些SZ和ASD基因表达的显著影响将HS以及可能的其他细胞应激源与致病遗传变异置于一个共同的概念框架中。研究结果还表明，基于少量阳性遗传学发现，一些被认为对SZ和ASD发病机制影响相对有限的候选基因，如SMARCA 2和ARNT 2，实际上可能在这些疾病中发挥更重要的作用-作为常见环境压力的目标。
Schizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.
登录
查看更多内容
影响因子：
3.7
作者：
Beck IM;Drebert ZJ;Hoya-Arias R;Bahar AA;Devos M;Clarisse D;Desmet S;Bougarne N;Ruttens B;Gossye V;Denecker G;Lievens S;Bracke M;Tavernier J;Declercq W;Gevaert K;Vanden Berghe W;Haegeman G;De Bosscher K
通讯作者：
De Bosscher K
影响因子：
6.6
作者：
Djurovic, Srdjan;Gustafsson, Omar;Andreassen, Ole A.
通讯作者：
Andreassen, Ole A.
影响因子：
9.3
作者：
El-Ansary A;Al-Ayadhi L
通讯作者：
Al-Ayadhi L
DOI：
10.1073/pnas.0703806104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Benes, Francine M.;Lim, Benjamin;Minns, Martin
通讯作者：
Minns, Martin
影响因子：
3.7
作者：
Ducharme, Guillaume;Lowe, Germaine C.;Williams, Sylvain
通讯作者：
Williams, Sylvain