Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
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DOI：
10.1038/s41593-018-0266-2
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发表时间：
2018-12-01
影响因子：
25
通讯作者：
Novarino, Gaia
中科院分区：
文献类型：
--
作者：
Deliu, Elena;Arecco, Niccolo;Novarino, Gaia
SETD 5基因突变已被确定为特发性智力残疾的常见原因。在这里，我们发现Setd 5-haploinsufficient小鼠存在发育缺陷，如异常的脑体重比和神经嵴缺陷相关的表型。此外，Setd 5突变小鼠表现出认知任务，增强的长时程增强，超声发声的个体发育特征延迟和行为不稳定性的障碍。行为问题伴随着先前与认知相关的突触后密度蛋白的异常表达。我们的数据还表明，Setd 5通过与Hdac 3和Paf 1复合物的相互作用来调节RNA聚合酶II动力学和基因转录，这一发现可能解释了在Setd 5-haploinsufficient小鼠中观察到的基因表达缺陷。我们的研究结果强调了Setd 5在智力残疾和自闭症谱系障碍患者中被破坏的生物学途径中的决定性作用。
SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder.