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Facultative dosage compensation of developmental genes on autosomes in Drosophila and mammals [RIP-seq]

ABSTRACT: Haploinsufficiency and aneuploidy are two phenomena, where alteration of gene dosage causes severe cellular defects ultimately resulting in developmental failures and disease. One remarkable exception is the X chromosome, where copy number differences between males and females are buffered through the action of dosage compensation systems. In Drosophila, the Male-Specific Lethal complex (MSLc) mediates two-fold upregulation of the single male X chromosome via Histone H4 lysine 16 acetylation (H4K16ac). The evolutionary origin and conservation of this process orchestrated by MSL2, the only male-specific protein within the fly MSLc, have remained unclear. Here, we report that MSL2, in addition to its function on the X, targets dosage-sensitive autosomal genes involved in patterning and morphogenesis. We show that the precise regulation of these genes by MSL2 is required for proper development of the fly wing. This set of dosage sensitive genes maintained such regulation during evolution, as MSL2 binds and similarly regulates mouse orthologues via deposition of H4K16ac. We propose that MSL2-mediated H4K16ac is an evolutionarily conserved process mediating gene-by-gene dosage compensation across flies and mammals.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE109900 | GEO | 2018/06/29

REPOSITORIES: GEO

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Facultative dosage compensation of developmental genes on autosomes in Drosophila and mammals [ChIP-seq Dmel]

Project description:Haploinsufficiency and aneuploidy are two phenomena, where alteration of gene dosage causes severe cellular defects ultimately resulting in developmental failures and disease. One remarkable exception is the X chromosome, where copy number differences between males and females are buffered through the action of dosage compensation systems. In Drosophila, the Male-Specific Lethal complex (MSLc) mediates two-fold upregulation of the single male X chromosome via Histone H4 lysine 16 acetylation (H4K16ac). The evolutionary origin and conservation of this process orchestrated by MSL2, the only male-specific protein within the fly MSLc, have remained unclear. Here, we report that MSL2, in addition to its function on the X, targets dosage-sensitive autosomal genes involved in patterning and morphogenesis. We show that the precise regulation of these genes by MSL2 is required for proper development of the fly wing. This set of dosage sensitive genes maintained such regulation during evolution, as MSL2 binds and similarly regulates mouse orthologues via deposition of H4K16ac. We propose that MSL2-mediated H4K16ac is an evolutionarily conserved process mediating gene-by-gene dosage compensation across flies and mammals.

2018-06-29 | GSE109898 | GEO

Facultative dosage compensation of developmental genes on autosomes in Drosophila and mammals [ChIP-seq mouse]

2018-06-29 | GSE109897 | GEO

Facultative dosage compensation of developmental genes on autosomes in Drosophila and mammals [RNA-seq mouse]

2018-06-29 | GSE109899 | GEO

The zinc finger protein CLAMP promotes long-range chromatin interactions that mediate dosage compensation of the Drosophila male X-chromosome [Hi-C seq]

Project description:Hi-C and 4C-seq anlaysis of Drosophila S2 cells Drosophila dosage compensation is an important model system for defining how active chromatin domains are formed. The Male-specific lethal dosage compensation complex (MSLc) increases transcript levels of genes along the length of the single male X-chromosome to equalize with that on the two female X-chromosomes. The strongest binding sites for MSLc cluster together in three-dimensional space independent of MSLc because clustering occurs in both sexes. CLAMP, a non-sex specific, ubiquitous zinc finger protein, binds synergistically with MSLc to enrich the occupancy of both factors on the male X-chromosome. Here, we demonstrate that CLAMP promotes the observed clustering of MSLc bindings sites. Genome-wide, CLAMP promotes interactions between active chromatin regions and represses interactions between inactive chromatin regions. Moreover, the X-enriched CLAMP protein promotes longer-range interactions on the active X-chromosome than autosomes. Overall, we define how long-range interactions, mediated by a locally-enriched ubiquitous transcription factor, generate a three-dimensional active chromatin domain.

2019-12-01 | GSE130545 | GEO

The zinc finger protein CLAMP promotes long-range chromatin interactions that mediate dosage compensation of the Drosophila male X-chromosome [4C-seq]

2019-12-01 | GSE130544 | GEO

Targeting of the dosage-compensated male X-chromosome during early Drosophila development

Project description:The essential process of dosage compensation, which corrects for the imbalance in X-linked gene expression between XX females and XY males, represents a key model for how genes are targeted for coordinated regulation. However, the mechanism by which dosage compensation complexes identify the X-chromosome during early development remained unknown because of the difficulty of sexing embryos prior to zygotic transcription. We used meiotic drive to sex Drosophila embryos prior to zygotic transcription and ChIP-seq to measure dynamics of dosage compensation factor targeting. The Drosophila Male-Specific Lethal dosage compensation complex (MSLc) requires the ubiquitous zinc-finger protein Chromatin-Linked Adaptor for MSL Proteins (CLAMP) to identify the X-chromosome. We observe a multi-stage process in which MSLc first identifies CLAMP binding sites throughout the genome followed by concentration at the strongest X-linked MSLc sites. We provide insight into the dynamic mechanism by which a large transcription complex identifies its binding sites during early development.

2019-12-01 | GSE133637 | GEO

Outcomes of MSL2 domain-swap mutation in mouse embryonic stem cells

Project description:Confinement of the X chromosome into a territory for dosage compensation (DC) is a prime example of subnuclear compartmentalization for transcription regulation at the megabase scale. In D. melanogaster, two sex-specific non-coding (nc) RNAs roX1 and roX2 are transcribed from the X chromosome. They associate with the Male-specific lethal (MSL) complex, which by acetylating histone H4 lysine 16 (H4K16ac) confers approximately 2-fold upregulated expression of male X-linked genes. Current models explain X-over-autosome specificity based on the MSL2 subunit recognizing cis-regulatory DNA high-affinity sites (HAS). However, HAS motifs are also found on autosomes, indicating that additional factors have evolved to confer stable association of the MSL complex with the X. Here, we show that the low-complexity C-terminal domain (CTD) of MSL2 renders its recruitment to the X chromosome sensitive to roX ncRNAs. roX-MSL2-CTD form a stably condensated state, and functional analyses in Drosophila and mammalian cells reveal the critical importance of their interplay for DC in vivo. Replacing the CTD of mammalian MSL2 with that from Drosophila and expressing roX in cis is sufficient to nucleate ectopic DC in mammalian cells. Thus, the condensating nature of roX-MSL2CTD is the primary determinant for specific compartmentalization of the X in Drosophila.

2020-08-07 | GSE129831 | GEO

Outcomes of MSL complex mutations on X chromosome dosage compensation by RNA-Seq

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Outcomes of MSL complex mutations on X chromosome dosage compensation by ChIP

2020-08-07 | GSE129795 | GEO

RNA nucleation by MSL2 induces selective compartmentalization of the X chromosome

2020-08-07 | GSE129834 | GEO