Molecular characterization of the male-specific lethal-3 gene and investigations of the regulation of dosage compensation in Drosophila

Development ◽  
1995 ◽  
Vol 121 (2) ◽  
pp. 463-475 ◽  
Author(s):  
M. Gorman ◽  
A. Franke ◽  
B.S. Baker
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
The Other ◽  
Single Male ◽  
X Chromosomes ◽  
Male Specific Lethal ◽  
Male Specific ◽  
Chromosome Binding

In Drosophila, dosage compensation occurs by transcribing the single male X chromosome at twice the rate of each of the two female X chromosomes. This hypertranscription requires four autosomal male-specific lethal (msl) genes and is negatively regulated by the Sxl gene in females. Two of the msls, the mle and msl-1 genes, encode proteins that are associated with hundreds of specific sites along the length of the male X chromosome. MLE and MSL-1 X chromosome binding are negatively regulated by Sxl in females and require the functions of the other msls in males. To investigate further the regulation of dosage compensation and the role of the msls in this process, we have cloned and molecularly characterized another msl, the msl-3 gene. We have found that MSL-3 is also associated with the male X chromosome. We have further investigated whether Sxl negatively regulates MSL-3 X-chromosome binding in females and whether MSL-3 X-chromosome binding requires the other msls. Our results suggest that the MLE, MSL-1 and MSL-3 proteins may associate with one another in a male-specific heteromeric complex on the X chromosome to achieve its hypertranscription.

The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex specifically regulated by Sex-lethal

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3245-3258 ◽  
Author(s):  
G.J. Bashaw ◽  
B.S. Baker
Keyword(s):  
Dna Binding ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Ring Finger ◽  
The Other ◽  
Male Specific Lethal ◽  
Alternatively Spliced ◽  
Sex Lethal ◽  
Specific Regulation ◽  
Male Specific

In Drosophila dosage compensation increases the rate of transcription of the male's X chromosome and depends on four autosomal male-specific lethal genes. We have cloned the msl-2 gene and shown that MSL-2 protein is co-localized with the other three MSL proteins at hundreds of sites along the male polytene X chromosome and that this binding requires the other three MSL proteins. msl-2 encodes a protein with a putative DNA-binding domain: the RING finger. MSL-2 protein is not produced in females and sequences in both the 5′ and 3′ UTRs are important for this sex-specific regulation. Furthermore, msl-2 pre-mRNA is alternatively spliced in a Sex-lethal-dependent fashion in its 5′ UTR.

Evidence that MSL-mediated dosage compensation in Drosophila begins at blastoderm

Development ◽  
1996 ◽  
Vol 122 (9) ◽  
pp. 2751-2760 ◽  
Author(s):  
A. Franke ◽  
A. Dernburg ◽  
G.J. Bashaw ◽  
B.S. Baker
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Dependent Manner ◽  
Gene Products ◽  
Histone H4 ◽  
Single Male ◽  
Somatic Tissues ◽  
Male Specific Lethal ◽  
Male Specific ◽  
Blastoderm Stage

In Drosophila equalization of the amounts of gene products produced by X-linked genes in the two sexes is achieved by hypertranscription of the single male X chromosome. This process, dosage compensation, is controlled by a set of male-specific lethal (msl) genes, that appear to act at the level of chromatin structure. The properties of the MSL proteins have been extensively studied in the polytene salivary gland chromosomes where they bind to the same set of sites along the male X chromosome in a co-dependent manner. Here we report experiments that show that the MSL proteins first associate with the male X chromosome as early as blastoderm stage, slightly earlier than the histone H4 isoform acetylated at lysine 16 is detected on the X chromosome. MSL binding to the male X chromosome is observed in all somatic tissues of embryos and larvae. Binding of the MSLs to the X chromosome is also interdependent in male embryos and prevented in female embryos by the expression of Sex-lethal (Sxl). A delayed onset of binding of the MSLs in male progeny of homozygous mutant msl-1 or mle mothers coupled with the previous finding that such males have an earlier lethal phase supports the idea that msl-mediated dosage compensation begins early in embryogenesis. Other results show that the maleless (MLE) protein on embryo and larval chromosomes differs in its reactivity with antibodies; the functional significance of this finding remains to be explored.

scholarly journals The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation

2021 ◽  
Author(s):  
Henrik Lindehell ◽  
Alexander Glotov ◽  
Eshagh Dorafshan ◽  
Yuri B Schwartz ◽  
Jan Larsson
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Specific Gene ◽  
H3k36 Methylation ◽  
Trithorax Group ◽  
Male Specific Lethal ◽  
Group Protein ◽  
Male Specific ◽  
Transcriptional Output

In Drosophila, two chromosomes require special mechanisms to balance their transcriptional output to the rest of the genome. These are the male-specific lethal complex targeting the male X-chromosome, and Painting of fourth targeting chromosome 4. The two systems are evolutionarily linked to dosage compensation of the X-chromosome and the chromosomes involved display specific chromatin structures. Here we explore the role of histone H3 tri-methylated at lysine 36 (H3K36me3) and the associated methyltransferases in these two chromosome-specific systems. We show that the loss of Set2 impairs the MSL complex mediated dosage compensation; however, the effect is not recapitulated by H3K36 replacement and indicates an alternative target of Set2. Unexpectedly, balanced transcriptional output from the 4th chromosome requires intact H3K36 and depends on the additive functions of NSD and the Trithorax group protein Ash1. We conclude that H3K36 methylation and the associated methyltransferases are important factors to balance transcriptional output of the male X-chromosome and the 4th chromosome. Furthermore, our study highlights the pleiotropic effects of these enzymes.

scholarly journals Absence of X-chromosome dosage compensation in the primordial germ cells of Drosophila embryos

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryoma Ota ◽  
Makoto Hayashi ◽  
Shumpei Morita ◽  
Hiroki Miura ◽  
Satoru Kobayashi
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Dosage Compensation ◽  
Sex Chromosome ◽  
Primordial Germ Cells ◽  
Histone H4 ◽  
X Chromosomes ◽  
Essential Components ◽  
Msl Complex ◽  
Male Specific

AbstractDosage compensation is a mechanism that equalizes sex chromosome gene expression between the sexes. In Drosophila, individuals with two X chromosomes (XX) become female, whereas males have one X chromosome (XY). In males, dosage compensation of the X chromosome in the soma is achieved by five proteins and two non-coding RNAs, which assemble into the male-specific lethal (MSL) complex to upregulate X-linked genes twofold. By contrast, it remains unclear whether dosage compensation occurs in the germline. To address this issue, we performed transcriptome analysis of male and female primordial germ cells (PGCs). We found that the expression levels of X-linked genes were approximately twofold higher in female PGCs than in male PGCs. Acetylation of lysine residue 16 on histone H4 (H4K16ac), which is catalyzed by the MSL complex, was undetectable in these cells. In male PGCs, hyperactivation of X-linked genes and H4K16ac were induced by overexpression of the essential components of the MSL complex, which were expressed at very low levels in PGCs. Together, these findings indicate that failure of MSL complex formation results in the absence of X-chromosome dosage compensation in male PGCs.

scholarly journals Drosophila CLAMP is an essential protein with sex-specific roles in males and females

2016 ◽  
Author(s):  
Jennifer A. Urban ◽  
Caroline A. Doherty ◽  
William T. Jordan ◽  
Jacob E. Bliss ◽  
Jessica Feng ◽  
...  
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Zinc Finger Protein ◽  
Pericentric Heterochromatin ◽  
Single Male ◽  
Essential Protein ◽  
Msl Complex ◽  
Males And Females ◽  
Male Specific

AbstractDosage compensation is a fundamental mechanism in many species that corrects for the inherent imbalance in X-chromosome copy number between XY males and XX females. In Drosophila melanogaster, transcriptional output from the single male X-chromosome is equalized to that of XX females by recruitment of the Male Specific Lethal (MSL) complex to specific sequences along the length of the X-chromosome. The initial recruitment of MSL complex to the X-chromosome is dependent on a recently discovered zinc finger protein called Chromatin-Linked Adapter for MSL Proteins (CLAMP). However, further studies on the in vivo function of CLAMP remained difficult because the location of the gene in pericentric heterochromatin made it challenging to create null mutations or deficiencies. Using the CRISPR/Cas9 genome editing system, we generated the first null mutant in the clamp gene that eliminates expression of CLAMP protein. We show that CLAMP is necessary for both male and female viability. While females die at the third instar larval stage, males die earlier, likely due to the essential role of CLAMP in male dosage compensation. Moreover, we demonstrate that CLAMP promotes dosage compensation in males and represses key male-specific transcripts involved in sex-determination in females. Our results reveal that CLAMP is an essential protein with dual roles in males and females, which together assure that dosage compensation is a sex-specific process.

scholarly journals Painting of Fourth and the X-Linked 1.688 Satellite in D. melanogaster Is Involved in Chromosome-Wide Gene Regulation

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 323
Author(s):  
Samaneh Ekhteraei-Tousi ◽  
Jacob Lewerentz ◽  
Jan Larsson
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Rapid Evolution ◽  
Regulatory Mechanisms ◽  
Expression Of Genes ◽  
Male Specific Lethal ◽  
Msl Complex ◽  
Specific Regulation ◽  
Male Specific ◽  
Genomic Regions

Chromosome-specific regulatory mechanisms provide a model to understand the coordinated regulation of genes on entire chromosomes or on larger genomic regions. In fruit flies, two chromosome-wide systems have been characterized: The male-specific lethal (MSL) complex, which mediates dosage compensation and primarily acts on the male X-chromosome, and Painting of fourth (POF), which governs chromosome-specific regulation of genes located on the 4th chromosome. How targeting of one specific chromosome evolves is still not understood; but repeated sequences, in forms of satellites and transposable elements, are thought to facilitate the evolution of chromosome-specific targeting. The highly repetitive 1.688 satellite has been functionally connected to both these systems. Considering the rapid evolution and the necessarily constant adaptation of regulatory mechanisms, such as dosage compensation, we hypothesised that POF and/or 1.688 may still show traces of dosage-compensation functions. Here, we test this hypothesis by transcriptome analysis. We show that loss of Pof decreases not only chromosome 4 expression but also reduces the X-chromosome expression in males. The 1.688 repeat deletion, Zhr1 (Zygotic hybrid rescue), does not affect male dosage compensation detectably; however, Zhr1 in females causes a stimulatory effect on X-linked genes with a strong binding affinity to the MSL complex (genes close to high-affinity sites). Lack of pericentromeric 1.688 also affected 1.688 expression in trans and was linked to the differential expression of genes involved in eggshell formation. We discuss our results with reference to the connections between POF, the 1.688 satellite and dosage compensation, and the role of the 1.688 satellite in hybrid lethality.

Regulation of domains and whole chromosomes

2019 ◽  
pp. 104-122
Author(s):  
John C. Lucchesi
Keyword(s):  
X Chromosome ◽  
Ribosomal Rna ◽  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Extreme Case ◽  
The Other ◽  
Histone Genes ◽  
Mammalian Embryo ◽  
X Chromosomes ◽  
Coordinate Regulation

Clusters of genes that encode similar products, such as the β‎-globin, the ribosomal RNA (rRNA) and the histone genes, are regulated in a coordinated fashion. An extreme case of coordinate regulation—dosage compensation—involves the genes present on the sex chromosomes. In Drosophila males, a complex (MSL) associates with the X chromosome where it enhances the activity of most X-linked genes. In Caenorhabditis, a complex (DCC) decreases the level of transcription of both X chromosomes in the XX hermaphrodite. In mammals, dosage compensation is achieved by the inactivation, early during development, of most X-linked genes on one of the two X chromosomes in females. In the mammalian embryo, X inactivation of either X chromosome is random and clonally inherited. The mechanism involves the synthesis of an RNA (Tsix) that protects one of the two Xs from inactivation, and of another RNA (Xist) that coats the other X chromosome and recruits histone- and DNA-modifying enzymes.

scholarly journals Attempts to test the inactive-X theory of dosage compensation in mammals

1963 ◽  
Vol 4 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Mary F. Lyon
Keyword(s):  
X Chromosome ◽  
Adult Female ◽  
Dosage Compensation ◽  
Somatic Cells ◽  
Coat Colour ◽  
The Other ◽  
Wild Type ◽  
X Chromosomes ◽  
Female Mice ◽  
Colour Mutant

The inactive-X theory of dosage compensation postulates that in all somatic cells of adult female mammals one or other of the two X chromosomes is genetically inactive. This means that in a female heterozygous for two non-allelic genes acting through the same cells, and carried one on each X chromosome, one or other gene should act in all cells. Conversely, if the two genes are carried on the same X, then both genes should act in some cells and neither gene in the remainder. This point has been tested by breeding experiments with mice, using pairs of genes affecting coat colour and coat texture. In female mice carrying the colour mutant dappled, Modp, on one X and a translocation including the wild-type alleles of pink-eye, p, and albino, c, on the other, either Modp or the translocation acted in all cells. With the genes tabby, Ta and striated, Str, affecting coat texture, in Str + / + Ta females tabby acted only in the non-Str patches, while in StrTa/ + + it acted only in the Str ones. Thus these experiments confirm that only one of the two X chromosomes is active in the somatic cells of female mammals.

scholarly journals CLAMP directly interacts with MSL2 to facilitate Drosophila dosage compensation

2018 ◽  
Author(s):  
Evgeniya Tikhonova ◽  
Anna Fedotova ◽  
Artem Bonchuk ◽  
Vladic Mogila ◽  
Erica N. Larschan ◽  
...  
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Protein Complexes ◽  
Dna Binding Protein ◽  
Zinc Finger Domain ◽  
Dosage Compensation Complex ◽  
Dna Interactions ◽  
Male Specific Lethal ◽  
Msl Complex ◽  
Male Specific

AbstractThe binding of Drosophila male-specific lethal (MSL) dosage compensation complex exclusively to male X chromosome provides an excellent model system to understand mechanisms of selective recruitment of protein complexes to chromatin. Previous studies showed that the male-specific organizer of the complex, MSL2, and ubiquitous DNA-binding protein CLAMP are key players in the specificity of X chromosome binding. The CXC domain of MSL2 binds to genomic sites of MSL complex recruitment. Here we demonstrated that MSL2 directly interacts with the N-terminal zinc-finger domain of CLAMP. CLAMP-MSL2 and CXC-DNA interactions are cooperatively involved in recruitment of MSL complex to the X chromosome.

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