Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
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DOI：
10.1172/jci.insight.163454
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发表时间：
2023-03-08
期刊：
影响因子：
8
通讯作者：
Mack, Christopher P.
中科院分区：
文献类型：
--
作者：
Zou, Meng;Mangum, Kevin D.;Magin, Justin C.;Cao, Heidi H.;Yarboro, Michael T.;Shelton, Elaine L.;Taylor, Joan M.;Reese, Jeff;Furey, Terrence S.;Mack, Christopher P.
基于我们的研究表明，平滑肌细胞选择性甲基转移酶Prdm6与肌钙蛋白相关的转录因子-A相互作用，我们利用细胞类型特异的基因敲除小鼠模型，研究了Prdm6‘S在体内SMC中的作用。尽管成年小鼠可以很好地耐受SMC特异性的Prdm6缺失，但在发育过程中表达WNT1的细胞中Prdm6缺失会导致围产期死亡和动脉导管未闭(DA)表型完全穿透。Wnt1Cre2 Prdm6fl/fl ROSA26LacZ小鼠的谱系追踪实验表明，流出道神经沟来源的SMC投资正常。相反，从E18.5胚胎分离的DA节段的肌图测量表明，Prdm6缺失显著降低了DA张力和收缩能力。对E18.5的DA和升主动脉样本的RNA-Seq分析证实了一个DA丰富的基因程序，其中包括许多受Prdm6缺失下调的SMC选择性收缩相关蛋白。流出道SMC的染色质免疫沉淀测序实验表明，改变的Prdm6缺失基因中有50%含有Prdm6结合位点。最后，使用几个全基因组数据集，我们在Prdm6第三内含子中发现了一个SMC选择性增强子，显示出等位基因特异性活性，提供了证据，证明rs17149944可能是人类PRDM6基因中确定的心血管疾病Gwas基因座的原因SNP。
Based upon our demonstration that the smooth muscle cell–selective (SMC-selective) putative methyltransferase, Prdm6, interacts with myocardin-related transcription factor-A, we examined Prdm6’s role in SMCs in vivo using cell type–specific knockout mouse models. Although SMC-specific depletion of Prdm6 in adult mice was well tolerated, Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype. Lineage tracing experiments in Wnt1Cre2 Prdm6fl/fl ROSA26LacZ mice revealed normal neural crest–derived SMC investment of the outflow tract. In contrast, myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility. RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion. Chromatin immunoprecipitation–sequencing experiments in outflow tract SMCs demonstrated that 50% of the genes Prdm6 depletion altered contained Prdm6 binding sites. Finally, using several genome-wide data sets, we identified an SMC-selective enhancer within the Prdm6 third intron that exhibited allele-specific activity, providing evidence that rs17149944 may be the causal SNP for a cardiovascular disease GWAS locus identified within the human PRDM6 gene.
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DOI：
10.1093/bioinformatics/btp527
发表时间：
2009-11-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lassmann T;Hayashizaki Y;Daub CO
通讯作者：
Daub CO
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
8
作者：
Hong L;Li N;Gasque V;Mehta S;Ye L;Wu Y;Li J;Gewies A;Ruland J;Hirschi KK;Eichmann A;Hendry C;van Dijk D;Mani A
通讯作者：
Mani A
影响因子：
4.6
作者：
Creemers, Esther E.;Sutherland, Lillian B.;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
4.8
作者：
Boucher, Joshua M.;Peterson, Sarah M.;Liaw, Lucy
通讯作者：
Liaw, Lucy