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BL6Mousei: MSL2 is an allelic dosage sensor in mammals

ABSTRACT: Allele-specific gene expression have been observed in genomic imprinting, X chromosome inactivation, allelic exclusion of immunoglobulin loci and non-canonical random monoallelic expression. Here we show that MSL2 can regulate allele specific gene expression and we elucidate its mechanism of action. MSL2 is known to regulate gene dosage up to two fold in drosophila and mammals. In addition to its canonical role as a milder modulator, we found that the loss of MSL2 switches off gene expression completely in an allele specific way and results in biallelic to monoallelic gene expression, which will be ignored as classical down regulated genes without applying the mouse hybrid F1 system. It indicates that MSL2 can activate the expression of the allele which is otherwise inactive intrinsically. We further found this is achieved by the interplay between MSL and KANSL complex. MSL2 acts as a methylation-insensitive factor, which can prevent DNA methylation of the inactive allele, thus facilitating occupancy of methylation-sensitive factor KANSL3 and activating the gene expression. The novel mechanism of MSL2 provides a safeguarding system to warrant biallelic gene expression of intrinsically monoallelic expressed genes including X-inactivated and imprinting genes. These genes are further discovered as sex bias genes such as X-inactivation escaped genes (escapees) are expressed higher in females. Furthermore, the biallelic expression of MSL2 regulated escapees may protect females from single loss of function mutation and contribute to male severer or predominance neurodevelopmental diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE231588 | GEO | 2023/08/10

REPOSITORIES: GEO

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Project description:The two copies of a gene are canonically believed to be indistinguishable to the cell and are expressed in the same spatiotemporal manner in the absence of a loss-of-function mutation. The mechanisms by which cells break this symmetry and express a gene from only one of the two alleles of the diploid genome are of great interest. Monoallelic gene expression on the X-chromosome, at imprinted genes, and at olfactory receptor genes has been studied in detail and involves combinations of non-coding RNAs, DNA methylation, and histone modifications. Recently, random monoallelic gene expression (RME), in which a gene can be expressed from either or both alleles in a clonal manner, has been described across many cell types and disease-relevant genes. However little is known about how RME is established and regulated. Here we develop allele-specific ATAC-seq, a rapid and sensitive method for profiling active regulatory DNA allelically and genome-wide, and find that monoallelic chromatin accessibility is extensive, developmentally regulated, and epigenetically inherited. In clonal hybrid F1 murine neural progenitor cells, we find over 1800 monoallelically-accessible DNA elements across autosomes. Randomly monoallelic regulatory elements tend to be promoter-proximal and located at RME genes identified by RNA-seq. Following differentiation, they are highly stable across passages and bookmarked during mitosis. Most RME genes have monoallelic promoters, but surprisingly, the nearby enhancer landscape around RME genes is biallelic. This suggests that RME genes are regulated at the chromatin, not post-transcriptional level, and that highly localized promoter accessibility is the gatekeeper within a permissive regulatory landscape dictating monoallelic vs. biallelic expression. These randomly monoallelic promoters are biallelically accessible in a previous developmental state, indicating that one allele is randomly shut down during NPC specification. Furthermore, the distribution of active alleles for a subset of these randomly monoallelic regulatory elements across clones deviates from a binomial distribution, indicating a highly regulated, non-stochastic mechanism of establishment.

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BL6Mousei: MSL2 is an allelic dosage sensor in mammals

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