MSL2 ensures biallelic gene expression in mammals

Yidan Sun, Meike Wiese, Raed Hmadi, Remzi Karayol, Janine Seyfferth, Juan Alfonso Martinez Greene, Niyazi Umut Erdogdu, Ward Deboutte, Laura Arrigoni, Herbert Holz, Gina Renschler, Naama Hirsch, Arion Foertsch, Maria Felicia Basilicata, Thomas Stehle, Maria Shvedunova, Chiara Bella, Cecilia Pessoa Rodrigues, Bjoern Schwalb, Patrick Cramer, Thomas Manke and Asifa Akhtar ()
Additional contact information
Yidan Sun: Max Planck Institute of Immunobiology and Epigenetics
Meike Wiese: Max Planck Institute of Immunobiology and Epigenetics
Raed Hmadi: Max Planck Institute of Immunobiology and Epigenetics
Remzi Karayol: Max Planck Institute of Immunobiology and Epigenetics
Janine Seyfferth: Max Planck Institute of Immunobiology and Epigenetics
Juan Alfonso Martinez Greene: Max Planck Institute of Immunobiology and Epigenetics
Niyazi Umut Erdogdu: Max Planck Institute of Immunobiology and Epigenetics
Ward Deboutte: Max Planck Institute of Immunobiology and Epigenetics
Laura Arrigoni: Max Planck Institute of Immunobiology and Epigenetics
Herbert Holz: Max Planck Institute of Immunobiology and Epigenetics
Gina Renschler: Max Planck Institute of Immunobiology and Epigenetics
Naama Hirsch: Max Planck Institute of Immunobiology and Epigenetics
Arion Foertsch: Max Planck Institute of Immunobiology and Epigenetics
Maria Felicia Basilicata: Max Planck Institute of Immunobiology and Epigenetics
Thomas Stehle: Max Planck Institute of Immunobiology and Epigenetics
Maria Shvedunova: Max Planck Institute of Immunobiology and Epigenetics
Chiara Bella: Max Planck Institute of Immunobiology and Epigenetics
Cecilia Pessoa Rodrigues: Max Planck Institute of Immunobiology and Epigenetics
Bjoern Schwalb: Max Planck Institute for Multidisciplinary Sciences
Patrick Cramer: Max Planck Institute for Multidisciplinary Sciences
Thomas Manke: Max Planck Institute of Immunobiology and Epigenetics
Asifa Akhtar: Max Planck Institute of Immunobiology and Epigenetics

Nature, 2023, vol. 624, issue 7990, 173-181

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06781-3

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