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. Whole-brain transcriptome of Myt1l heterozygote mutation mice age of P3, P21 and P56Myt1l是一种在发育过程中参与神经元诱导与维持的转录因子，且与自闭症谱系障碍（autism spectrum disorder, ASD）密切相关。本研究中，携带外显子9杂合缺失的Myt1l突变型成年小鼠，表现出轻度类自闭症行为（社交缺陷与特定重复行为），同时还存在多动、抗焦虑样行为等额外行为异常。为探究这些行为异常背后的分子模式与作用机制，我们对野生型与Myt1l突变型小鼠的全脑组织开展了RNA测序（RNA-seq）分析，采样覆盖了从幼崽期（约P3）、青少年期（约P21）至成年期（约P56）的纵向时间进程。幼崽期的Myt1l突变小鼠，其染色体与染色质相关基因呈现表达上调，而突触及神经递质相关基因则表达下调。自青少年期起，Myt1l突变小鼠的细胞外基质与转运蛋白相关基因表达上调，线粒体及核糖体相关基因表达下调。此外，幼崽期的Myt1l突变小鼠呈现促自闭症的转录组特征，但从青少年期至成年期，这类特征逐渐逆转，转变为抗自闭症的转录组模式，这大概率属于代偿性变化。上述结果表明，Myt1l的单倍体剂量不足会快速将转录组模式改变为促自闭症类型，并通过长期代偿过程调控突触成熟。本数据集包含P3、P21及P56三个年龄段的Myt1l杂合突变小鼠全脑组织转录组数据。