Brain transcriptome analysis of Myt1l heterozygote mutation mice (RNA-Seq I)

Myt1l is a transcription factor for neuronal induction and maintenance during development and Myt1l is highly implicated in autism spectrum disorder (ASD). Myt1l-mutant mice with a heterozygous deletion of exon 9 showed mild autistic-like behaviors (Social deficit and specific repetitive behaviors) and additional behavioral abnormalities including hyperactivity and anxiolytic-like behaviors in adult. To explore the molecular patterns and mechanisms underlying these behavioral abnormalities, we performed RNA-seq analysis of whole brain from wild-type and Myt1l-mutant mice longitudinally from pup stage (~P3) to juvenile (~P21) and adult (~P56) stages. Myt1l-mutant mice showed upregulations of chromosome- and chromatin-related genes and downregulations of synapse- and neurotransmitter-related genes during pup stage. However, from juvenile stage, Myt1l-mutant mice showed upregulations of extracellular matrix- and transporter-related genes and downregulations of mitochondria- and ribosome-related genes. In addition, Myt1l-mutant mice showed pro-ASD transcriptomic patterns on pup stage, but these patterns were reversed toward anti-ASD transcriptomic patterns from juvenile stages to adult stage as compensatory changes likely. These results suggest that the haploinsufficiency of Myt1l acutely alters the transcriptomic pattern into pro-ASD patterns and chronically compensates with the synapse maturation. Overall design: Whole-brain transcriptome of Myt1l heterozygote mutation mice age of P3, P21 and P56

Myt1l是一种在发育进程中参与神经元诱导与维持的转录因子（transcription factor），且与自闭症谱系障碍（Autism Spectrum Disorder, ASD）密切相关。携带外显子9（exon 9）杂合缺失的Myt1l突变型小鼠，在成年阶段表现出轻度类自闭症行为（社交缺陷与特异性重复行为），同时还存在多动、类抗焦虑行为等其他行为异常。为探究上述行为异常背后的分子模式与调控机制，我们对野生型与Myt1l突变小鼠的全脑组织开展了RNA测序（RNA-seq）分析，采样时间纵向覆盖幼崽期（约P3）、青少年期（约P21）及成年期（约P56）三个发育阶段。幼崽期的Myt1l突变小鼠中，染色体与染色质相关基因呈现上调表达，而突触及神经递质相关基因则出现下调表达。然而自青少年期起，Myt1l突变小鼠的细胞外基质与转运体相关基因呈现上调表达，线粒体与核糖体相关基因则出现下调表达。此外，幼崽期的Myt1l突变小鼠呈现促自闭症谱系障碍的转录组模式，但从青少年期至成年期，这类模式逐渐向抗自闭症谱系障碍的转录组模式转变，这大概率是一种代偿性变化。上述结果表明，Myt1l的单倍体剂量不足（haploinsufficiency）会快速将转录组模式改变为促自闭症谱系障碍模式，并通过长期代偿调控突触成熟过程。整体实验设计：对P3、P21及P56月龄的Myt1l杂合突变小鼠进行全脑转录组分析。