The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Dev Cell. 2012 Sep 11;23(3):652-63. doi: 10.1016/j.devcel.2012.07.010. Epub 2012 Aug 23.
DiGeorge syndrome, caused by a 22q11 microdeletion or mutation of the TBX1 gene, varies in severity greatly, even among monozygotic twins. Epigenetic phenomena have been invoked to explain phenotypic differences in individuals of identical genetic composition, although specific chromatin modifications relevant to DiGeorge syndrome are elusive. Here we show that lack of the histone acetyltransferase MOZ (MYST3/KAT6A) phenocopies DiGeorge syndrome, and the MOZ complex occupies the Tbx1 locus, promoting its expression and histone 3 lysine 9 acetylation. Importantly, DiGeorge syndrome-like anomalies are present in mice with homozygous mutation of Moz and in heterozygous Moz mutants when combined with Tbx1 haploinsufficiency or oversupply of retinoic acid. Conversely, a Tbx1 transgene rescues the heart phenotype in Moz mutants. Our data reveal a molecular mechanism for a specific chromatin modification of the Tbx1 locus intersecting with an environmental determinant, modeling variability in DiGeorge syndrome.
DiGeorge 综合征是由 22q11 微缺失或 TBX1 基因突变引起的，其严重程度差异很大，即使在同卵双胞胎中也是如此。表观遗传现象被用来解释具有相同遗传组成的个体之间的表型差异，尽管与 DiGeorge 综合征相关的特定染色质修饰仍然难以捉摸。在这里，我们表明缺乏组蛋白乙酰转移酶 MOZ（MYST3/KAT6A）可模拟 DiGeorge 综合征，并且 MOZ 复合物占据 Tbx1 基因座，促进其表达和组蛋白 3 赖氨酸 9 乙酰化。重要的是，在同源性突变的 Moz 小鼠和杂合性 Moz 突变体与 Tbx1 杂合不足或视黄酸过量结合时，存在 DiGeorge 综合征样异常。相反，Tbx1 转基因可挽救 Moz 突变体的心脏表型。我们的数据揭示了 Tbx1 基因座的特定染色质修饰与环境决定因素相互作用的分子机制，为 DiGeorge 综合征的变异性建模。
