Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk.
Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk.
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DOI：
10.1371/journal.pgen.1007681
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发表时间：
2018-10
期刊：
影响因子：
4.5
通讯作者：
Quertermous T
中科院分区：
文献类型：
--
作者：
Iyer D;Zhao Q;Wirka R;Naravane A;Nguyen T;Liu B;Nagao M;Cheng P;Miller CL;Kim JB;Pjanic M;Quertermous T
尽管通过全基因组关联研究已发现许多基因位点与冠状动脉疾病（CAD）相关，但仍需努力确定这些位点中的致病基因，并将它们与基本的信号通路联系起来。近期研究调查了CAD相关基因SMAD3的疾病机制，SMAD3是转化生长因子β（TGFβ）通路中的一个核心转录因子（TF），研究其在平滑肌生物学中的作用。对人冠状动脉平滑肌细胞（HCASMC）的体外研究表明，SMAD3调节细胞表型，促进分化标记基因的表达，同时抑制增殖。在HCASMC中进行的RNA测序和染色质免疫沉淀测序研究确定了下游基因，这些基因位于介导该细胞类型中血管发育和动脉粥样硬化过程的通路中。与另一个CAD相关转录因子TCF21相比，HCASMC表型以及由SMAD3促进的基因表达模式具有相反的作用方向。在DNA上SMAD3和TCF21共定位的位点，SMAD3的结合与TCF21的结合呈负相关，部分原因是TCF21在局部阻断了SMAD3结合位点的染色质可及性。此外，在转染报告基因研究中，TCF21能够直接抑制SMAD3对基因表达的激活。与对CAD具有保护作用的TCF21相反，HCASMC中的SMAD3表达与疾病风险直接相关。我们提出，SMAD3的促分化作用抑制了去分化，而去分化是HCASMC在应对血管应激时扩张和稳定疾病斑块所必需的，从而抵消了TCF21的保护性去分化活性并促进了疾病风险。
冠状动脉疾病（CAD）是全球首要的死亡原因。CAD的大部分风险本质上是遗传性的，即遗传信息的一个特征，由父母双方传递给每个个体，主要影响血管壁中的疾病过程，这些过程调节疾病的分子通路。现代遗传学方法已能够绘制人类基因组中编码介导这种风险信息的区域图谱。通过这些研究已确定了SMAD3基因，它是其他基因和分子通路的已知主要调控因子，我们已经研究了该基因对疾病风险具有重要作用的功能。SMAD3影响血管壁的一个细胞成分——平滑肌细胞（SMC）的基本功能，SMC负责对血管应激作出反应，以修复与血脂升高和其他经典风险因素相关的病变。此处报道的研究表明，SMAD3实际上抑制了允许SMC修复血管病变的细胞过程，并且其在基因组疾病相关区域中的表达由疾病相关的可变序列所促进。SMAD3受到另一个CAD基因TCF21的拮抗，TCF21的作用是阻断SMAD3表达的影响，这些研究确定了实现这一作用的遗传机制。因此，这些研究确定了一个直接导致疾病风险的相互作用通路，并且阻断SMAD3或促进TCF21功能的能力可被利用来抑制诸如心肌梗死等血管事件。
Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk. Coronary artery disease (CAD) is the worldwide leading cause of death. The majority of risk for CAD is genetic in nature, i.e., a feature of the genetic information that is transmitted to each individual from both parents, and primarily affects the disease processes in the blood vessel wall that regulate the disease molecular pathways. Modern genetic approaches have allowed mapping of the regions of the human genome that encode information that mediates this risk. The SMAD3 gene has been identified through these studies, a known master regulatory of other genes and molecular pathways, and we have investigated the functions of this gene that are important for disease risk. SMAD3 affects basic functions of a cellular component of the vessel wall, the smooth muscle cell (SMC), that is responsible for responding to vascular stresses to heal the lesions that are produced in conjunction with elevated lipids and other classic risk factors. Studies reported here show that SMAD3 actually inhibits the cellular processes that allow SMC to repair the vascular lesions, and its expression is promoted by the disease related variable sequences in the disease associated regions of the genome. SMAD3 is opposed by another CAD gene, TCF21, that functions to block the effects of SMAD3 expression, and these studies identify genetic mechanisms by which this is done. Thus, these studies identify an interactive pathway that directly contributes to disease risk, and the ability to block SMAD3 or promote TCF21 function could be exploited to inhibit vascular events such as myocardial infarction.
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影响因子：
20.1
作者：
Compton, Leigh A.;Potash, Dru A.;Barnett, Joey V.
通讯作者：
Barnett, Joey V.
英国生物库中的遗传分析将胰岛素抵抗和跨内皮迁移途径与冠状动脉疾病联系起来。
影响因子：
30.8
作者：
Klarin D;Zhu QM;Emdin CA;Chaffin M;Horner S;McMillan BJ;Leed A;Weale ME;Spencer CCA;Aguet F;Segrè AV;Ardlie KG;Khera AV;Kaushik VK;Natarajan P;CARDIoGRAMplusC4D Consortium;Kathiresan S
通讯作者：
Kathiresan S
影响因子：
30.8
作者：
Howson JMM;Zhao W;Barnes DR;Ho WK;Young R;Paul DS;Waite LL;Freitag DF;Fauman EB;Salfati EL;Sun BB;Eicher JD;Johnson AD;Sheu WHH;Nielsen SF;Lin WY;Surendran P;Malarstig A;Wilk JB;Tybjærg-Hansen A;Rasmussen KL;Kamstrup PR;Deloukas P;Erdmann J;Kathiresan S;Samani NJ;Schunkert H;Watkins H;CARDIoGRAMplusC4D;Do R;Rader DJ;Johnson JA;Hazen SL;Quyyumi AA;Spertus JA;Pepine CJ;Franceschini N;Justice A;Reiner AP;Buyske S;Hindorff LA;Carty CL;North KE;Kooperberg C;Boerwinkle E;Young K;Graff M;Peters U;Absher D;Hsiung CA;Lee WJ;Taylor KD;Chen YH;Lee IT;Guo X;Chung RH;Hung YJ;Rotter JI;Juang JJ;Quertermous T;Wang TD;Rasheed A;Frossard P;Alam DS;Majumder AAS;Di Angelantonio E;Chowdhury R;EPIC-CVD;Chen YI;Nordestgaard BG;Assimes TL;Danesh J;Butterworth AS;Saleheen D
通讯作者：
Saleheen D
影响因子：
20.1
作者：
Kobayashi, K;Yokote, K;Saito, Y
通讯作者：
Saito, Y
DOI：
10.1126/science.aad6970
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franzén O;Ermel R;Cohain A;Akers NK;Di Narzo A;Talukdar HA;Foroughi-Asl H;Giambartolomei C;Fullard JF;Sukhavasi K;Köks S;Gan LM;Giannarelli C;Kovacic JC;Betsholtz C;Losic B;Michoel T;Hao K;Roussos P;Skogsberg J;Ruusalepp A;Schadt EE;Björkegren JL
通讯作者：
Björkegren JL