德国马克斯·普朗克免疫生物学和表观遗传学研究所Asifa Akhtar团队发现，MSL2可确保哺乳动物中双拷贝基因的表达。这一研究成果于2023年11月29日在线发表在国际学术期刊《自然》上。
研究人员确定了MSL2在哺乳动物中调节等位基因表达的作用。在小鼠神经祖细胞中进行的等位基因特异性大量和单细胞分析表明，除了显示双等位基因下调的靶点外，还有一类基因在MSL2缺失后从双等位基因表达过渡到单等位基因表达。其中许多基因是单倍表达的。在MSL2缺失的情况下，一个等位基因保持活性，保留活性组蛋白修饰和转录因子结合，而另一个等位基因则沉默，表现出启动子-增强子接触的丧失和DNA甲基化的获得。
Msl2-基因敲除小鼠在胚胎发育过程中表现出围产期致死和异质性表型，支持了MSL2在调节基因剂量中的作用。MSL2在保持特定剂量敏感基因的双倍表达中的作用为进一步研究哺乳动物细胞中参与等位基因剂量补偿的其他因素奠定了基础，并对人类疾病具有重大意义。
据介绍，在二倍体生物中，双倍体基因的表达能够产生足够水平的mRNA。这对单倍体基因至关重要，因为单倍体基因需要双倍体表达才能发挥最佳功能，以防止发育障碍的发生。至于在单个基因位点上是否以及如何，以细胞类型特异性的方式决定双复制或单复制状态，目前仍不清楚。MSL2在果蝇雄性X染色体的剂量补偿中是已知的。
附：英文原文
Title: MSL2 ensures biallelic gene expression in mammals
Author: Sun, Yidan, Wiese, Meike, Hmadi, Raed, Karayol, Remzi, Seyfferth, Janine, Martinez Greene, Juan Alfonso, Erdogdu, Niyazi Umut, Deboutte, Ward, Arrigoni, Laura, Holz, Herbert, Renschler, Gina, Hirsch, Naama, Foertsch, Arion, Basilicata, Maria Felicia, Stehle, Thomas, Shvedunova, Maria, Bella, Chiara, Pessoa Rodrigues, Cecilia, Schwalb, Bjoern, Cramer, Patrick, Manke, Thomas, Akhtar, Asifa
Issue&Volume: 2023-11-29
Abstract: In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA1,2. This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders1,3. Whether and how a biallelic or monoallelic state is determined in a cell-type-specific manner at individual loci remains unclear. MSL2 is known for dosage compensation of the male X chromosome in flies. Here we identify a role of MSL2 in regulating allelic expression in mammals. Allele-specific bulk and single-cell analyses in mouse neural progenitor cells revealed that, in addition to the targets showing biallelic downregulation, a class of genes transitions from biallelic to monoallelic expression after MSL2 loss. Many of these genes are haploinsufficient. In the absence of MSL2, one allele remains active, retaining active histone modifications and transcription factor binding, whereas the other allele is silenced, exhibiting loss of promoter–enhancer contacts and the acquisition of DNA methylation. Msl2-knockout mice show perinatal lethality and heterogeneous phenotypes during embryonic development, supporting a role for MSL2 in regulating gene dosage. The role of MSL2 in preserving biallelic expression of specific dosage-sensitive genes sets the stage for further investigation of other factors that are involved in allelic dosage compensation in mammalian cells, with considerable implications for human disease.
