Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice
Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice
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DOI：
10.1172/jci43428
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Thiel, Christian Thomas
中科院分区：
文献类型：
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作者：
Kraft, Michael;Cirstea, Ion Cristian;Thiel, Christian Thomas
通过组蛋白的共价修饰对基因表达进行表观遗传调控是控制生长发育的关键过程。因此，调控这些过程的转录因子是遗传病的重要靶点。然而，令人惊讶的是，人们对异常的表观遗传状态、受影响的细胞过程及其表型后果之间的关系知之甚少。通过对一例Noonan综合征样表型患者的染色体断裂点作图，包括身材矮小、眼睑下垂和注意缺陷多动障碍，我们确定组蛋白乙酰转移酶基因myst组蛋白乙酰转移酶4(MYST4)单倍体不足是该表型的潜在原因。利用乙酰化、全基因组表达和对患者细胞、使用siRNA下调MYST4表达的细胞系和Myst4 quetkopf小鼠的芯片研究，我们发现H3乙酰化对神经、颅面和骨骼的形态发生很重要，主要是通过其特异性调节MAPK信号通路的能力。这一发现进一步阐明了组蛋白修饰在哺乳动物发育中的复杂作用，并为RAS信号通路的错误调节导致的致病表型增加了一种新的机制。
Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.