MSL2 ensures biallelic gene expression in mammals

• Published in: Nature (London) 2023-12, Vol.624 (7990), p.173-181
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/106; 38; 45/100; 45/15; 45/77; 45/91; 631/114/1314; 631/136/142; 631/208/176; 631/208/177; Alleles; Animals; Cells (biology); Compensation; Diploids; DNA methylation; DNA-Binding Proteins - metabolism; Dosage; Dosage compensation; Dosage Compensation, Genetic; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Embryogenesis; Embryonic growth stage; Gene dosage; Gene Expression; Genes; Histones; Humanities and Social Sciences; Humans; Lethality; Male; Mammalian cells; Mammals; Mammals - genetics; Mammals - metabolism; Mice; Mice, Knockout; multidisciplinary; Neural stem cells; Nuclear Proteins - metabolism; Phenotypes; Progenitor cells; Science; Science (multidisciplinary); Transcription Factors - metabolism; Ubiquitin-Protein Ligases - metabolism; X chromosomes
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06781-3

In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA 1 , 2 . This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders 1 , 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. After loss of MSL2, a class of dosage-sensitive genes transitions from biallelic to monoallelic expression, whereby one allele remains active, retaining active histone modifications and transcription factor binding, and the other allele is silenced, exhibiting loss of promoter–enhancer contacts and the acquisition of DNA methylation.