近日，美国加州大学教授Nicole G. Coufal团队的最新研究探明了MEF2C在人小胶质细胞中的转录和表观遗传靶点参与与自闭症风险和年龄相关疾病相关的细胞功能。2025年10月22日，国际知名学术期刊《自然—免疫学》发表了这一成果。

为了研究MEF2C在人类小胶质细胞中的疾病相关功能，小组分析了MEF2C单倍缺失和MEF2C敲除诱导的多能干细胞系分化的小胶质细胞。互补转录组学和功能分析显示，MEF2C的缺失导致高炎症表型，包括广泛的吞噬功能障碍、脂质积累、溶酶体功能障碍和基础炎症细胞因子分泌升高。MEF2C结合位点的全基因组分析加上活跃的调控景观，可以推断其转录功能和MEF2C相关细胞功能的潜在机制。

转录组学和表观遗传学方法发现了与特发性自闭症数据集的大量重叠，表明人类小胶质细胞MEF2C失调在特发性自闭症中发挥了更广泛的作用。在单主题异种移植模型中，MEF2C的缺失导致体内人小胶质细胞形态、溶酶体和脂质异常。总之，这些研究揭示了减少小胶质细胞MEF2C可能促进神经系统疾病发展的机制。

据悉，MEF2C编码一种在神经系统发育中起关键作用的转录因子。

附：英文原文

Title: Transcriptional and epigenetic targets of MEF2C in human microglia contribute to cellular functions related to autism risk and age-related disease

Author: Nguyen, Celina, Broersma, Emily H., Warden, Anna S., Mora, Cristina, Han, Claudia Z., Keulen, Zahara, Spann, Nathanael, Wang, Jing, Ramirez, Gabriela, Mak, Samantha, Trescott, Samantha, Khakpour, Mohammadparsa, Johnson, Avalon, Qureshi, Fatir, La Frano, Michael R., Mohajeri, Kiana, Talkowski, Michael E., Corradin, Olivia, Tremblay, Marie-ve, Glass, Christopher K., Coufal, Nicole G.

Issue&Volume: 2025-10-22

Abstract: MEF2C encodes a transcription factor that is critical in nervous system development. Here, to examine disease-associated functions of MEF2C in human microglia, we profiled microglia differentiated from isogenic MEF2C-haploinsufficient and MEF2C-knockout induced pluripotent stem cell lines. Complementary transcriptomic and functional analyses revealed that loss of MEF2C led to a hyperinflammatory phenotype with broad phagocytic impairment, lipid accumulation, lysosomal dysfunction and elevated basal inflammatory cytokine secretion. Genome-wide profiling of MEF2C-bound sites coupled with the active regulatory landscape enabled inference of its transcriptional functions and potential mechanisms for MEF2C-associated cellular functions. Transcriptomic and epigenetic approaches identified substantial overlap with idiopathic autism datasets, suggesting a broader role of human microglial MEF2C dysregulation in idiopathic autism. In a mouse xenotransplantation model, loss of MEF2C led to morphological, lysosomal and lipid abnormalities in human microglia in vivo. Together, these studies reveal mechanisms by which reduced microglial MEF2C could contribute to the development of neurological diseases.

DOI: 10.1038/s41590-025-02299-0

Source: https://www.nature.com/articles/s41590-025-02299-0