CaBl: MSL2 is an allelic dosage sensor in mammals
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE183766 | GEO | 2023/08/10
REPOSITORIES: GEO
Similar Datasets
Project description:Biallelic expression is important to ensure adequate mRNA levels as well as protect cells from deleterious heterozygous mutations. However, the factors determining biallelic expression at individual gene loci are unknown. Deletion of the MSL complex component MSL2 in hybrid mouse NPCs uncovers an unprecedented function for MSL2 in allelic regulation. While biallelically expressed in wildtype NPCs, a class of MSL2 targets switches from bi to monoallelic expression upon MSL2 loss. The silenced allele loses nascent transcription, accompanied by dramatic changes in local chromatin landscape such as monoallelic gain of H3K27me3 and DNA methylation. Meanwhile, active histone modifications, RNA POL II, BRD4 and KANSL3 are retained on the active allele. MSL2 targets include several sex-biased genes on autosomes as well as X-chromosomal genes that escape X inactivation. Together, the allele-specific resolution allowed us to unravel an MSL2 mediated safeguarding mechanism to promote biallelic gene expression of sexually dimorphic and dosage-sensitive genes in mammals.
2023-08-10 | GSE183765 | GEO
Project description:Biallelic expression is important to ensure adequate mRNA levels as well as protect cells from deleterious heterozygous mutations. However, the factors determining biallelic expression at individual gene loci are unknown. Deletion of the MSL complex component MSL2 in hybrid mouse NPCs uncovers an unprecedented function for MSL2 in allelic regulation. While biallelically expressed in wildtype NPCs, a class of MSL2 targets switches from bi to monoallelic expression upon MSL2 loss. The silenced allele loses nascent transcription, accompanied by dramatic changes in local chromatin landscape such as monoallelic gain of H3K27me3 and DNA methylation. Meanwhile, active histone modifications, RNA POL II, BRD4 and KANSL3 are retained on the active allele. MSL2 targets include several sex-biased genes on autosomes as well as X-chromosomal genes that escape X inactivation. Together, the allele-specific resolution allowed us to unravel an MSL2 mediated safeguarding mechanism to promote biallelic gene expression of sexually dimorphic and dosage-sensitive genes in mammals.
2023-08-10 | GSE183764 | GEO
Project description: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.
2023-08-10 | GSE231588 | GEO
Project description: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.
2023-08-10 | GSE227741 | GEO
Project description:We have studied the regulatory potential of MYST1-(MOF)-containing MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors. We find that both complexes influence transcription by binding to promoters as well as TSS-distal enhancer regions. In contrast to flies, the MSL complex is not enriched on the X chromosome yet it is crucial for mammalian X chromosome regulation as it specifically regulates Tsix ncRNA, the major repressor of Xist lncRNA. MSL depletion leads to severely decreased Tsix expression, reduced REX1 recruitment, and consequently accumulation of Xist RNA in ESCs. The NSL complex provides additional, Tsix-independent repression of Xist by maintaining pluripotency. MSL and NSL complexes therefore act synergistically by using distinct pathways to ensure a fail-safe mechanism for the repression of X inactivation in ESCs. We have performed ChIP-seq of KANSL3, MCRS1, MOF, MSL1 and MSL2 in mouse ESCs, and KANSL3, MOF and MSL2 in NPCs, in duplicate and normalised against their inputs. We have also performed RNA-seq following knockdown of Kansl3, Mof, Msl1 and Msl2 mouse embryonic stem cells in triplicate. NB: Kansl3 and Mof knockdown-RNAseq are analyzed against their own scrambled controls, and Msl1 and Msl2 against another scrambled control triplicate.
2014-06-03 | E-GEOD-57698 | biostudies-arrayexpress
Project description:We assessed the genome-wide binding of the histone acetylase MOF and members of its two associated complexes, the male-specific lethal and the non-specific lethal complex (MSL, NSL). We generated ChIP-seq profiles for MOF, MSL1, MSL2, KANSL3, and MCRS1 from mouse embryonic stem cells and neuronal progenitor cells. By using two replicates per sample and stringent filtering criteria, we identify five basic groups of genome regions where the proteins show either mutual or exclusive binding. We find that the NSL complex members (KANSL3, MCRS1) target the TSSs of broadly expressed genes with housekeeping functions in both cell types. MOF and particularly the MSL complex target a subset of these NSL-complex-targets, too. In addition, we find several thousand TSS-distal binding sites, particularly in ESCs, where KANSL3, MSL2 and MCRS1 show strong enrichments for annotated ESC enhancers. The vast majority of the binding to these ESC distal regulatory elements is lost in NPCs. Finally, we identify mostly intronic and intergenic regions with predominant MSL2 enrichments without the presence of its known interactors. These binding sites do not overlap with ESC marks of active chromatin (e.g. DNase hypersensitivity sites), but the they increase in number upon differentiation and we detect a strong signature of the (CAGA)n motif. Our study provides the first comprehensive analysis of MOF in the context of its two complexes in the mouse and reveals shared as well as distinct and dynamic functions for gene regulation and pluripotency. ChIP-seq of MOF and members of its associated complexes (MSL complex: MSL1, MSL2; NSL complex: KANSL3, MCRS1) in male mouse embryonic stem cells and neuronal progenitor cells derived from them.
2014-06-03 | E-GEOD-51746 | biostudies-arrayexpress
Project description:We used H83M2 P element to ectopically expressed MSL2 protein in females to test if the novel formed MSL complex is the directly reason of dosage compensation Compare the MSL2 females with normal females and normal males; MSL2 males also included.
2012-10-16 | E-GEOD-41570 | biostudies-arrayexpress
Project description:We assessed the genome-wide binding of the histone acetylase MOF and members of its two associated complexes, the male-specific lethal and the non-specific lethal complex (MSL, NSL). We generated ChIP-seq profiles for MOF, MSL1, MSL2, KANSL3, and MCRS1 from mouse embryonic stem cells and neuronal progenitor cells. By using two replicates per sample and stringent filtering criteria, we identify five basic groups of genome regions where the proteins show either mutual or exclusive binding. We find that the NSL complex members (KANSL3, MCRS1) target the TSSs of broadly expressed genes with housekeeping functions in both cell types. MOF and particularly the MSL complex target a subset of these NSL-complex-targets, too. In addition, we find several thousand TSS-distal binding sites, particularly in ESCs, where KANSL3, MSL2 and MCRS1 show strong enrichments for annotated ESC enhancers. The vast majority of the binding to these ESC distal regulatory elements is lost in NPCs. Finally, we identify mostly intronic and intergenic regions with predominant MSL2 enrichments without the presence of its known interactors. These binding sites do not overlap with ESC marks of active chromatin (e.g. DNase hypersensitivity sites), but the they increase in number upon differentiation and we detect a strong signature of the (CAGA)n motif. Our study provides the first comprehensive analysis of MOF in the context of its two complexes in the mouse and reveals shared as well as distinct and dynamic functions for gene regulation and pluripotency.
2014-06-03 | GSE51746 | GEO
Project description:Drosophila males double transcription of their single X chromosome to equalize X-linked gene expression with females, which carry two X chromosomes. Increased transcription requires the Male-Specific Lethal (MSL) complex. The MSL2 protein is essential component of the MSL complex. MSL2 is the only protein that is strictly limited to males. MSL2 together with MSL1 forms the core of the MSL complex. The global effect of msl2 mutation on gene expression was measured by microarray analysis. We found that expression of the X chromosome was decreased in msl21 male larvae, supporting the involvement of MSL2 in the up-regulation of X-linked genes. However, there was no change in expression of 4th chromosomal and heterochromatic genes. This finding is broadly comparable to reports of reduced X chromosome expression following msl2 RNAi knockdown in S2 cells. Hence MSL2 is required for up-regulation of male X chromosome where as it is not necessary for normal expression of 4th chromosomal genes and heterochromatic genes in Drosophila melanogaster males.
2009-08-03 | GSE12054 | GEO
Project description:We used H83M2 P element to ectopically expressed MSL2 protein in females to test if the novel formed MSL complex is the directly reason of dosage compensation
2012-10-16 | GSE41570 | GEO