The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues.
The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues.
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DOI：
10.1093/g3journal/jkac104
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发表时间：
2022-05-30
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影响因子：
--
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中科院分区：
文献类型：
--
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基因表达的遗传调控在组织类型和个体之间差异很大，并且可能受到环境的强烈影响。在健康对照条件下，许多变体可能是沉默的，甚至在患病应激条件下具有相反的效果。本研究使用体内小鼠模型来研究遗传变异的影响如何随着不同组织的细胞应激而变化。当错误折叠的蛋白质在内质网中积累时，发生内质网应激。这触发了未折叠的蛋白质反应，这是一种试图恢复体内平衡的大的转录反应。这种转录反应，尽管是一个保守的，基本的细胞过程，是高度可变的不同的遗传背景，使其成为一个理想的系统来研究遗传变异的动态影响。在这项研究中，我们试图更好地了解遗传变异如何改变组织中的表达，在存在和不存在内质网应激。使用不同的小鼠品系和它们的F1代也使我们能够鉴定在可变的转录应答下的背景特异性顺式和反式调节变异。我们发现了数百个以组织和/或基因型依赖的方式对内质网应激作出反应的基因。我们发现的大多数调节作用都是顺式作用，这反过来又导致了可变的内质网应激和组织特异性转录反应。这项研究表明，在未来的研究中，需要将环境应激因子纳入多个不同的组织中，以更好地阐明任何特定遗传因子在基本生物学途径中的作用，如内质网应激反应。
The genetic regulation of gene expression varies greatly across tissue-type and individuals and can be strongly influenced by the environment. Many variants, under healthy control conditions, may be silent or even have the opposite effect under diseased stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with cellular stress across different tissues. Endoplasmic reticulum stress occurs when misfolded proteins accumulate in the endoplasmic reticulum. This triggers the unfolded protein response, a large transcriptional response which attempts to restore homeostasis. This transcriptional response, despite being a conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study the dynamic effects of genetic variation. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of endoplasmic reticulum stress. The use of different mouse strains and their F1s allow us to also identify context-specific cis- and trans- regulatory variation underlying variable transcriptional responses. We found hundreds of genes that respond to endoplasmic reticulum stress in a tissue- and/or genotype-dependent manner. The majority of the regulatory effects we identified were acting in cis-, which in turn, contribute to the variable endoplasmic reticulum stress- and tissue-specific transcriptional response. This study demonstrates the need for incorporating environmental stressors across multiple different tissues in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the endoplasmic reticulum stress response.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
9.9
作者：
Grishkevich, Vladislav;Ben-Elazar, Shay;Hashimshony, Tamar;Schott, Daniel H.;Hunter, Craig P.;Yanai, Itai
通讯作者：
Yanai, Itai
影响因子：
9.8
作者：
Dombroski, Beth A.;Nayak, Renuka R.;Spielman, Richard S.
通讯作者：
Spielman, Richard S.
影响因子：
5.4
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
DOI：
10.1073/pnas.0914072107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Auf, Gregor;Jabouille, Arnaud;Moenner, Michel
通讯作者：
Moenner, Michel