Haploinsufficiency of SETD5 is implicated in syndromic autism spectrum disorder (ASD), but the molecular mechanism underlying the pathological role of this protein has remained unclear. We have now shown that Setd5^+/– mice manifest ASD-related behavioral phenotypes and that the expression of ribosomal protein genes and rDNA is disturbed in the brain of these mice. SETD5 recruited the HDAC3 complex to the rDNA promoter, resulting in removal of the histone mark H4K16ac and its reader protein TIP5, a repressor of rDNA expression. Depletion of SETD5 attenuated rDNA expression, translational activity, and neural cell proliferation, whereas ablation of TIP5 in SETD5-deficient cells rescued these effects. Translation of cyclin D1 mRNA was specifically down-regulated in SETD5-insufficient cells. Our results thus suggest that SETD5 positively regulates rDNA expression via an HDAC3-mediated epigenetic mechanism and that such regulation is essential for translation of cyclin D1 mRNA and neural cell proliferation.

SETD5的单倍剂量不足与综合征性自闭症谱系障碍（ASD）有关，但尚不清楚该蛋白的病理作用所依据的分子机制。现在我们已经显示Setd5 ^+/-小鼠表现出与ASD相关的行为表型，这些小鼠的大脑中核糖体蛋白基因和rDNA的表达受到干扰。SETD5将HDAC3复合物募集到rDNA启动子，导致去除了组蛋白标记H4K16ac及其阅读器蛋白TIP5（rDNA表达的阻遏物）。SETD5的耗竭减弱了rDNA的表达，翻译活性和神经细胞的增殖，而SETD5缺乏的细胞中TIP5的消融挽救了这些作用。在SETD5不足的细胞中，细胞周期蛋白D1 mRNA的翻译被特异性下调。因此，我们的结果表明，SETD5通过HDAC3介导的表观遗传机制正调控rDNA的表达，并且这种调控对于细胞周期蛋白D1 mRNA的翻译和神经细胞增殖至关重要。