The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy
The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy
复制标题
组蛋白甲基转移酶混合谱系白血病 (MLL) 3 可能在临床扩张型心肌病中发挥潜在作用
DOI：
10.2119/molmed.2017.00012
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发表时间：
2017-01-01
影响因子：
5.7
通讯作者：
Wei, Xiang
中科院分区：
文献类型：
--
作者：
Jiang, Ding-Sheng;Yi, Xin;Wei, Xiang
组蛋白修饰在扩张型心肌病（DCM）的病理过程中起着关键作用，而组蛋白甲基转移酶（hmt），特别是混合谱系白血病（MLL）家族在DCM中的作用和表达模式尚不清楚。为此，本研究纳入了12例正常心脏和15例DCM心脏样本。采用横断主动脉缩窄法（TAC）建立小鼠心脏重构模型。采用实时聚合酶链反应检测小鼠和人左心室MLL家族的表达水平。在TAC手术处理的小鼠心脏中，MLL3 mRNA水平显著升高。与正常心脏相比，DCM心脏中MLL3 mRNA和蛋白表达水平较高，其表达水平与左室舒张末期内径和左室射血分数密切相关。而其他MLL家族（MLL、MLL2、MLL4、MLL5、SETD1A和SETD1B）在对照组和DCM心脏及重塑小鼠心脏中的表达水平无明显变化。此外，二甲基化组蛋白H3赖氨酸4 （H3K4me2）在DCM心脏中显著升高，而H3K4me3不显著升高。MLL3调控的Smad3、GATA4和EGR1蛋白水平在DCM心脏中显著升高。我们迄今未被认识的发现表明，MLL3通过调节H3K4me2和Smad3、GATA4和EGR1的表达，在DCM的病理过程中具有潜在的作用。
Histone modifications play a critical role in the pathological processes of dilated cardiomyopathy (DCM), while the role and expression pattern of histone methyltransferases (HMTs), especially mixed lineage leukemia (MLL) families, in DCM are unclear. To this end, 12 normal and 15 DCM heart samples were included in the present study. A murine cardiac remodeling model was induced by transverse aortic constriction (TAC). Real-time polymerase chain reaction was performed to detect the expression levels of MLL families in the mouse and human left ventricles. The mRNA level of MLL3 was significantly increased in the mouse hearts treated with TAC surgery. Compared with normal hearts, higher mRNA and protein level of MLL3 was detected in the DCM hearts, and its expression level was closely associated with left ventricular end diastolic diameter and left ventricular ejection fraction. However, there was no obvious change in the expression levels of other MLL families (MLL, MLL2, MLL4, MLL5, SETD1A and SETD1B) between control and DCM hearts or remodeled mouse hearts. Furthermore, the dimethylated histone H3 lysine 4 (H3K4me2) but not H3K4me3 was significantly increased in the DCM hearts. The protein levels of Smad3, GATA4 and EGR1, which might be regulated by MLL3, were remarkably elevated in the DCM hearts. Our hitherto unrecognized findings indicate that MLL3 has a potential role in the pathological processes of DCM by regulating H3K4me2 and the expression of Smad3, GATA4 and EGR1.