Characterizing genetic variation in the regulation of the ER stress response through computational and cis-eQTL analyses.
Characterizing genetic variation in the regulation of the ER stress response through computational and cis-eQTL analyses.
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DOI：
10.1093/g3journal/jkad229
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发表时间：
2023-12-06
影响因子：
2.6
通讯作者：
Chow, Clement Y.
中科院分区：
文献类型：
--
作者：
Russell, Nikki D.;Jorde, Lynn B.;Chow, Clement Y.
内质网（ER）中的错误折叠蛋白引起ER应激反应，这是一种由3种充分表征的转录因子（TF）驱动的大的转录反应。这种转录反应在不同的遗传背景中是可变的。遗传变异可导致ER应激反应中转录变异的一种机制是通过改变3种主要TF的结合和活性：XBP 1、ATF 6和ATF 4。这项工作试图通过首先创建一个计算管道来更好地理解这种机制，以确定整个人类基因组中的潜在结合位点。我们利用GTEx数据集来鉴定落入预测TF结合位点（TFBS）内的顺式eQTL。我们还利用ClinVar数据库来比较结合基序的不同位置处的致病性变体与良性变体的数量。最后，我们对经历ER应激的人类细胞系进行了顺式eQTL分析，以确定调节可变ER应激反应的顺式eQTL。这些顺式eQTL中的大多数对于给定的条件是独特的：对照或ER胁迫。这些胁迫特异性顺式eQTL中的一些落在3个主要ER胁迫响应TF的推定结合位点内，提供了这些顺式eQTL可能通过改变TF结合来影响ER胁迫条件下的基因表达的潜在机制。这项研究代表了对经历ER应激的人类样本的第一个顺式eQTL分析，并且是确定负责可变ER应激反应的遗传组分的重要一步。
Misfolded proteins in the endoplasmic reticulum (ER) elicit the ER stress response, a large transcriptional response driven by 3 well-characterized transcription factors (TFs). This transcriptional response is variable across different genetic backgrounds. One mechanism in which genetic variation can lead to transcriptional variability in the ER stress response is through altered binding and activity of the 3 main TFs: XBP1, ATF6, and ATF4. This work attempts to better understand this mechanism by first creating a computational pipeline to identify potential binding sites throughout the human genome. We utilized GTEx data sets to identify cis-eQTLs that fall within predicted TF binding sites (TFBSs). We also utilized the ClinVar database to compare the number of pathogenic vs benign variants at different positions of the binding motifs. Finally, we performed a cis-eQTL analysis on human cell lines experiencing ER stress to identify cis-eQTLs that regulate the variable ER stress response. The majority of these cis-eQTLs are unique to a given condition: control or ER stress. Some of these stress-specific cis-eQTLs fall within putative binding sites of the 3 main ER stress response TFs, providing a potential mechanism by which these cis-eQTLs might be impacting gene expression under ER stress conditions through altered TF binding. This study represents the first cis-eQTL analysis on human samples experiencing ER stress and is a vital step toward identifying the genetic components responsible for the variable ER stress response.
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影响因子：
4.5
作者：
Fogarty MP;Cannon ME;Vadlamudi S;Gaulton KJ;Mohlke KL
通讯作者：
Mohlke KL
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
DOI：
10.1093/bioinformatics/bty127
发表时间：
2018-07-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Ambrosini G;Groux R;Bucher P
通讯作者：
Bucher P
DOI：
10.1126/science.1183621
发表时间：
2010-04-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kasowski M;Grubert F;Heffelfinger C;Hariharan M;Asabere A;Waszak SM;Habegger L;Rozowsky J;Shi M;Urban AE;Hong MY;Karczewski KJ;Huber W;Weissman SM;Gerstein MB;Korbel JO;Snyder M
通讯作者：
Snyder M
影响因子：
5.3
作者：
Baumeister, P;Luo, SZ;Lee, AS
通讯作者：
Lee, AS