Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.
Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.
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Smyd1 通过拮抗氧化和内质网应激反应来促进心脏发育。
DOI：
10.1371/journal.pone.0121765
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tucker HO
中科院分区：
文献类型：
--
作者：
Rasmussen TL;Ma Y;Park CY;Harriss J;Pierce SA;Dekker JD;Valenzuela N;Srivastava D;Schwartz RJ;Stewart MD;Tucker HO
Smyd1/Bop是一种进化保守的组蛋白甲基转移酶，先前通过常规敲除显示对胚胎心脏发育至关重要。为了进一步探索细胞自主背景下的机制，我们使用敲入（KI） Nkx2.5-cre驱动程序有条件地消融小鼠第一和第二心区的Smyd1。心肌细胞和流出道（OFT）中flox - smyd1的强烈缺失导致胚胎在E9.5时死亡，OFT和右心室截断，以及与第二心田（SHF）扩张和增殖受损一致的额外缺陷。使用转基因（Tg） Nkx2.5-cre驱动，先前在SHF和OFT中显示不删除，绕过了早期胚胎致死，形成了两个心室；然而，心肌细胞增殖减少和其他心脏缺陷导致胚胎在11.5-12.5期后期死亡。在妊娠早期和中期死亡之前，增殖损伤伴随着内质网应激关键转录物的失调。妊娠中期死亡也与氧化应激防御损伤有关，这一表型与先前表征的smyd1相互作用转录因子skNAC的敲除高度相似。我们描述了一种潜在的反馈机制，当应激反应因子Tribbles3/TRB3被Smyd1直接甲基化时，它可以作为Smyd1介导的转录的共同抑制因子。我们的研究结果表明，Smyd1是维持心肌细胞增殖所必需的，至少在两个不同的胚胎心脏发育阶段，它的缺失导致相关的应激反应，这标志着随后的致命性。
Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense—a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
20.1
作者：
Avery J;Etzion S;DeBosch BJ;Jin X;Lupu TS;Beitinjaneh B;Grand J;Kovacs A;Sambandam N;Muslin AJ
通讯作者：
Muslin AJ
影响因子：
3.7
作者：
Foreman KW;Brown M;Park F;Emtage S;Harriss J;Das C;Zhu L;Crew A;Arnold L;Shaaban S;Tucker P
通讯作者：
Tucker P
影响因子：
4
作者：
Just, Steffen;Meder, Benjamin;Rottbauer, Wolfgang
通讯作者：
Rottbauer, Wolfgang
影响因子：
4.6
作者：
Galli, Daniela;Dominguez, Jorge N.;Buckingham, Margaret E.
通讯作者：
Buckingham, Margaret E.