Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming.
Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming.
复制标题
DOI：
10.1152/ajpheart.00728.2016
复制
发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Kathryn M. Spitler;Jessica M. Ponce;G. Oudit;D. Hall;Chad E. Grueter
中科院分区：
文献类型：
--
作者：
Kathryn M. Spitler;Jessica M. Ponce;G. Oudit;D. Hall;Chad E. Grueter
介体复合体是一种多亚基核复合体，作为转录因子和RNA聚合酶II之间的桥梁，在调节基因表达方面发挥着不可或缺的作用。介体亚单位1(MED1)的基因缺失会导致胚胎死亡，这在很大程度上是由于心脏发育受阻。我们首先建立了MED1在心脏发育和疾病中的动态表达，在人类和小鼠衰竭的心脏中MED1显著上调。为了确定MED1缺陷是否可以抵御心脏应激，我们建立了两种心脏特异的MED1基因敲除小鼠模型，其中MED1有条件地缺失(Med1cKO小鼠)或在成年小鼠(Med1cKO-MCM小鼠)中诱导缺失。在这两种模型中，心脏MED1基因缺失导致早期死亡，并伴有明显的心功能变化，包括左心室扩张、射血分数降低和病理结构重构。接下来，我们使用RNA测序分析定义了MED1缺陷如何改变心脏转录图谱。Med1cKO小鼠表现出与心脏代谢相关的基因显著失调，特别是由转录因子pgc1α、pparα和errα协调的基因。与这些转录因子在线粒体基因调控中的作用一致，我们观察到在MED1缺乏的情况下，线粒体大小、线粒体基因表达、复合体活性和电子传输链表达发生了显著变化。综上所述，这些数据证实MED1是重要的心脏基因表达和维持正常心脏功能的重要调节因子。新的和值得注意的转录基因表达中断是扩张型心肌病的标志；然而，其病因尚不清楚。心脏特异的转录辅活化子介体亚单位1(MED1)缺失会导致扩张型心肌病、心功能下降和致死性。MED1缺失打乱了心肌线粒体和代谢基因的表达模式。
The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function.NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.