Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard Medical School, Boston, MA, USA.
Mol Autism. 2020 Jun 5;11(1):45. doi: 10.1186/s13229-020-00354-1.
MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5.
To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5 mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models.
Gene expression analyses across three brain regions from Mbd5 mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function.
These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations.
Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes.
MBD5 编码甲基-CpG 结合域 5 蛋白，被认为是 2q23.1 微缺失综合征的必要和充分驱动因素。外显子组测序研究中的从头错义突变和蛋白截断变异直接将 MBD5 牵连到自闭症谱系障碍 (ASD) 和相关神经发育障碍 (NDD) 的病因中。然而，对于 MBD5 的具体功能知之甚少。
为了深入了解 ASD 和相关 NDD 个体中 MBD5 改变相关的复杂相互作用，我们探索了杂合功能减弱 Mbd5 小鼠模型的多个小鼠脑区的 MBD5 部分缺失的转录图谱，并将这些结果与 CRISPR 介导的人类 iPSC 衍生神经元模型中的 MBD5 突变进行了比较。
Mbd5 小鼠三个脑区的基因表达分析显示出微妙的转录变化，皮质显示出 Mbd5 减少后最广泛的变化，表明存在上下文依赖性效应。与人类神经元细胞中 MBD5 减少的比较强化了由于 MBD5 缺陷导致的基因表达变化的上下文依赖性。基因共表达网络分析揭示了与 MBD5 表达降低相关且富含与纤毛功能相关术语的基因簇。
这些分析包括有限数量的小鼠脑区和神经元模型，并且基因敲低的影响很细微。因此，这些结果不会反映 ASD 早期神经发育过程中 MBD5 破坏在人类大脑区域的全部程度，也无法捕捉到与 MBD5 改变相关的各种细胞类型特异性变化。
我们的研究表明大脑中 Mbd5 破坏的适度和上下文相关的转录后果。它还表明 MBD5 与纤毛功能紊乱之间可能存在联系，纤毛功能紊乱是发育障碍和综合征中的一种既定致病机制。
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