BEYOND EXPRESSION: MSL2'S KEY ROLE IN DOSAGE MAINTENANCE

 

As previously known, sexually reproducing organisms inherit one copy of a chromosome from their parents, making a diploid somatic cell. In general, most of the genes exhibit balanced expression from both maternal and paternal alleles. In the sense that only one allele is expressed. However, there are some exceptions like haploinsufficient genes that exhibit biallelic expression as two transcribing copies of the gene are essential to produce a functional amount of protein. Loss or mutation of one allele is more than enough to cause diseases. 

Males Of flies and mammals have distinct sex chromosome composition, X and Y chromosomes, making them heterogametic sex. This concludes that males have different chromosomes (XY) than females (XX). This makes the situation where certain genes of X are present in a single copy in males resulting in hemizygosity. 

To balance the X-linked expression a dosage compensation mechanism is used in mammals which is done by inactivation of the X chromosome in females. In flies this is quite different, MLS (Male-Specific Lethal) histone acetyltransferase complex is responsible for dosage compensation in males. This complex upregulates the transcription of genes on the single X chromosome in males, matching the expression levels of the two X chromosomes in females.

So, while mammals achieve dosage compensation through X chromosome inactivation in females, flies utilise the MSL complex to boost the expression of X-linked genes in males, thereby equalising gene expression between the sexes.

MSL2, a part of the MSL complex, engages with X-linked long non-coding RNAs to establish specificity for the lone male X chromosome in flies. This is further discussed in the paper “MSL2 ensures biallelic gene expression in mammals” in the journal, Nature. 

The paper suggests the idea that MSL2 has a conserved role in dipterans and mammals and is associated with regulating the dosage of developmental genes. 

Using hybrid mouse lines, it was discovered that MSL2 plays a crucial role in maintaining biallelic transcription for a specific gene subset known as "bi-to-mono genes." Often overlooked in standard analyses, these genes rely on MSL2 to preserve promoter–enhancer interactions. The loss of MSL2 disrupts these interactions, leading to monoallelic promoter DNA methylation, preventing methylation-sensitive transcription factor binding, and resulting in monoallelic loss of chromatin accessibility and transcriptional silencing. This sheds light on MSL2's multifaceted role in maintaining proper gene dosage.

Many bi-to-mono genes are haploinsufficient, potentially causing cellular dysfunction and human diseases. The data suggest that MSL2 acts as an anti-monoallelic factor, contributing to biallelic expression and maintaining appropriate gene dosage. MSL2 is proposed as one example of such a factor, acknowledging potential heterogeneity in target specificity among MSL2 targets. Future studies using hybrid in vivo models and in vitro systems with a larger number of clones are recommended for a more precise assessment.

In the absence of MSL2, DNA methylation occurs at the silenced allele, hindering CG-motif transcription factor binding. The hypothesis is that MSL2 prevents DNA methylation, creating a methylation-free environment for transcription factors similar to CTCF. Mechanistic exploration of MSL2's role in preventing DNA methylation and its interactions with other factors at the allele-specific level is crucial.

MSL2 loss disrupts allele-specific promoter–enhancer contacts, emphasizing their importance in allelic transcriptional activation. While some long-range enhancer–promoter contacts are disrupted at both alleles after MSL2 loss, others are monoallelically preserved, suggesting the involvement of additional factors. Further analysis of the spatial genome at the allele-specific level will unravel the regulation of biallelic versus monoallelic expression, potentially contributing to new therapeutic strategies for human diseases.

REFERENCE

Sun Y, Wiese M, Hmadi R, Karayol R, Seyfferth J, Martinez Greene JA, et al. MSL2 ensures biallelic gene expression in mammals. Nature. 2023;624(7990):173–81. doi:10.1038/s41586-023-06781-3