scholarly journals Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila

2021 ◽  
Vol 4 (9) ◽  
pp. e202000996
Author(s):  
Claudia Isabelle Keller Valsecchi ◽  
Eric Marois ◽  
M Felicia Basilicata ◽  
Plamen Georgiev ◽  
Asifa Akhtar
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Histone H4 ◽  
Ecological Constraints ◽  
Evolutionary Trajectory ◽  
X Chromosomes ◽  
Deleterious Gene ◽  
Msl Complex ◽  
High Degree

Sex chromosomes induce potentially deleterious gene expression imbalances that are frequently corrected by dosage compensation (DC). Three distinct molecular strategies to achieve DC have been previously described in nematodes, fruit flies, and mammals. Is this a consequence of distinct genomes, functional or ecological constraints, or random initial commitment to an evolutionary trajectory? Here, we study DC in the malaria mosquito Anopheles gambiae. The Anopheles and Drosophila X chromosomes evolved independently but share a high degree of homology. We find that Anopheles achieves DC by a mechanism distinct from the Drosophila MSL complex–histone H4 lysine 16 acetylation pathway. CRISPR knockout of Anopheles msl-2 leads to embryonic lethality in both sexes. Transcriptome analyses indicate that this phenotype is not a consequence of defective X chromosome DC. By immunofluorescence and ChIP, H4K16ac does not preferentially enrich on the male X. Instead, the mosquito MSL pathway regulates conserved developmental genes. We conclude that a novel mechanism confers X chromosome up-regulation in Anopheles. Our findings highlight the pluralism of gene-dosage buffering mechanisms even under similar genomic and functional constraints.

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.

Dosage Compensation of the X Chromosome: A Complex Epigenetic Assignment Involving Chromatin Regulators and Long Noncoding RNAs

2018 ◽  
Vol 87 (1) ◽  
pp. 323-350 ◽  
Author(s):  
Maria Samata ◽  
Asifa Akhtar
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Transcriptional Activation ◽  
Gene Dosage ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Histone H4 ◽  
Chromosome Conformation ◽  
Msl Complex ◽  
Male Specific

X chromosome regulation represents a prime example of an epigenetic phenomenon where coordinated regulation of a whole chromosome is required. In flies, this is achieved by transcriptional upregulation of X chromosomal genes in males to equalize the gene dosage differences in females. Chromatin-bound proteins and long noncoding RNAs (lncRNAs) constituting a ribonucleoprotein complex known as the male-specific lethal (MSL) complex or the dosage compensation complex mediate this process. MSL complex members decorate the male X chromosome, and their absence leads to male lethality. The male X chromosome is also enriched with histone H4 lysine 16 acetylation (H4K16ac), indicating that the chromatin compaction status of the X chromosome also plays an important role in transcriptional activation. How the X chromosome is specifically targeted and how dosage compensation is mechanistically achieved are central questions for the field. Here, we review recent advances, which reveal a complex interplay among lncRNAs, the chromatin landscape, transcription, and chromosome conformation that fine-tune X chromosome gene expression.

scholarly journals Parallel Universes for Models of X Chromosome Dosage Compensation in Drosophila: A Review

2016 ◽  
Vol 148 (1) ◽  
pp. 52-67 ◽  
Author(s):  
James A. Birchler
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Sex Chromosome ◽  
Fold Increase ◽  
Molecular Data ◽  
X Chromosomes ◽  
Histone Modifiers ◽  
Parallel Universes ◽  
Msl Complex ◽  
High Level

Dosage compensation in Drosophila involves an approximately 2-fold increase in expression of the single X chromosome in males compared to the per gene expression in females with 2 X chromosomes. Two models have been considered for an explanation. One proposes that the male-specific lethal (MSL) complex that is associated with the male X chromosome brings histone modifiers to the sex chromosome to increase its expression. The other proposes that the inverse effect which results from genomic imbalance would tend to upregulate the genome approximately 2-fold, but the MSL complex sequesters histone modifiers from the autosomes to the X to mute this autosomal male-biased expression. On the X, the MSL complex must override the high level of resulting histone modifications to prevent overcompensation of the X chromosome. Each model is evaluated in terms of fitting classical genetic and recent molecular data. Potential paths toward resolving the models are suggested.

scholarly journals Transcription-Coupled Methylation of Histone H3 at Lysine 36 Regulates Dosage Compensation by Enhancing Recruitment of the MSL Complex in Drosophila melanogaster

2008 ◽  
Vol 28 (10) ◽  
pp. 3401-3409 ◽  
Author(s):  
Oliver Bell ◽  
Thomas Conrad ◽  
Jop Kind ◽  
Christiane Wirbelauer ◽  
Asifa Akhtar ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Histone H3 ◽  
The Body ◽  
Histone H4 ◽  
Histone H3 Methylation ◽  
Msl Complex ◽  
Male Specific ◽  
Active Genes

ABSTRACT In Drosophila melanogaster, dosage compensation relies on the targeting of the male-specific lethal (MSL) complex to hundreds of sites along the male X chromosome. Transcription-coupled methylation of histone H3 lysine 36 is enriched toward the 3′ end of active genes, similar to the MSL proteins. Here, we have studied the link between histone H3 methylation and MSL complex targeting using RNA interference and chromatin immunoprecipitation. We show that trimethylation of histone H3 at lysine 36 (H3K36me3) relies on the histone methyltransferase Hypb and is localized promoter distal at dosage-compensated genes, similar to active genes on autosomes. However, H3K36me3 has an X-specific function, as reduction specifically decreases acetylation of histone H4 lysine 16 on the male X chromosome. This hypoacetylation is caused by compromised MSL binding and results in a failure to increase expression twofold. Thus, H3K36me3 marks the body of all active genes yet is utilized in a chromosome-specific manner to enhance histone acetylation at sites of dosage compensation.

scholarly journals The Drosophila MSL Complex Acetylates Histone H4 at Lysine 16, a Chromatin Modification Linked to Dosage Compensation

2000 ◽  
Vol 20 (1) ◽  
pp. 312-318 ◽  
Author(s):  
Edwin R. Smith ◽  
Antonio Pannuti ◽  
Weigang Gu ◽  
Arnd Steurnagel ◽  
Richard G. Cook ◽  
...  
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Chromatin Modification ◽  
Gene Products ◽  
Histone H4 ◽  
Linked Gene ◽  
Rna Transcripts ◽  
Msl Complex ◽  
Males And Females

ABSTRACT In Drosophila, dosage compensation—the equalization of most X-linked gene products in males and females—is achieved by a twofold enhancement of the level of transcription of the X chromosome in males relative to each X chromosome in females. A complex consisting of at least five gene products preferentially binds the X chromosome at numerous sites in males and results in a significant increase in the presence of a specific histone isoform, histone 4 acetylated at lysine 16. Recently, RNA transcripts (roX1 and roX2) encoded by two different genes have also been found associated with the X chromosome in males. We have partially purified a complex containing MSL1, -2, and -3, MOF, MLE, and roX2 RNA and demonstrated that it exclusively acetylates H4 at lysine 16 on nucleosomal substrates. These results demonstrate that the MSL complex is responsible for the specific chromatin modification characteristic of the X chromosome in Drosophila males.

scholarly journals X-chromosome inactivation: dosage compensation of genes or heterochromatin?

2019 ◽  
pp. 75-87
Author(s):  
AI Ibraimov
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Sex Chromosome ◽  
Gene Dosage ◽  
Alternative Hypothesis ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Inactive X Chromosome ◽  
Mammalian Female

X-chromosome inactivation (XCI) is the process by which one of two X chromosomes in mammalian female cells is inactivated. The DNA of the inactive X chromosome is packaged in transcriptionally inactive heterochromatin. It is generally accepted that XCI have evolved to enable dosage compensation in mammals as a way to equalize X-linked gene expression between XX and XY individuals. However, there remain several controversial issues regarding the causes of XCI. The most important of them, why dosage compensation of genes? An alternative hypothesis is discussed that XCI is caused by dose compensation for heterochromatin, rather than genes, in the genome of female mammals due to the lack of a sex chromosome in their karyotype with a large constitutive heterochromatin block, as in Y chromosome in males. It is for this reason that heterochromatinization of the euchromatin regions of one of the X chromosomes occurs. The biological meaning of heterochromatinization is to increase the density of condensed chromatin (??) around the interphase nucleus, responsible for removing excess heat from the nucleus into the cytoplasm, since the compaction of ?? depends on the amount of heterochromatin. The consequence of this process is the inactivation of genes that were in the area of heterochromatinization of the X chromosome. Keywords: X-chromosome inactivation; Lyonization; Gene dosage compensation; Heterochromatin dosage compensation; Cell thermoregulation

scholarly journals Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1114
Author(s):  
Ali Youness ◽  
Charles-Henry Miquel ◽  
Jean-Charles Guéry
Keyword(s):  
Autoimmune Diseases ◽  
X Chromosome ◽  
Gene Dosage ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Female Sex Hormones ◽  
Inactive X Chromosome ◽  
Immune Related Genes ◽  
Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

X chromosome gene dosage compensation in female mammals

1993 ◽  
Vol 4 (2) ◽  
pp. 129-139 ◽  
Author(s):  
Giuseppe Borsani ◽  
Andrea Ballabio
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Chromosome Gene

scholarly journals Contingency in the convergent evolution of a regulatory network: Dosage compensation in Drosophila

2018 ◽  
Author(s):  
Doris Bachtrog ◽  
Chris Ellison
Keyword(s):  
Transposable Element ◽  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Binding Sites ◽  
Evolutionary Biology ◽  
De Novo ◽  
Binding Motif ◽  
Sequence Motif ◽  
X Chromosomes ◽  
Msl Complex

The repeatability or predictability of evolution is a central question in evolutionary biology, and most often addressed in experimental evolution studies. Here, we infer how genetically heterogeneous natural systems acquire the same molecular changes, to address how genomic background affects adaptation in natural populations. In particular, we take advantage of independently formed neo-sex chromosomes in Drosophila species that have evolved dosage compensation by co-opting the dosage compensation (MSL) complex, to study the mutational paths that have led to the acquisition of 100s of novel binding sites for the MSL complex in different species. This complex recognizes a conserved 21-bp GA-rich sequence motif that is enriched on the X chromosome, and newly formed X chromosomes recruit the MSL complex by de novo acquisition of this binding motif. We identify recently formed sex chromosomes in the Drosophila repleta and robusta species groups by genome sequencing, and generate genomic occupancy maps of the MSL complex to infer the location of novel binding sites. We find that diverse mutational paths were utilized in each species to evolve 100s of de novo binding motifs along the neo-X, including expansions of microsatellites and transposable element insertions. However, the propensity to utilize a particular mutational path differs between independently formed X chromosomes, and appears to be contingent on genomic properties of that species, such as simple repeat or transposable element density. This establishes the “genomic environment” as an important determinant in predicting the outcome of evolutionary adaptations.

scholarly journals On the Mode of Gene-Dosage Compensation in Drosophila

Genetics ◽  
1997 ◽  
Vol 145 (3) ◽  
pp. 729-736
Author(s):  
Irina Arkhipova ◽  
Jingjing Li ◽  
Matthew Meselson
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Gene Activity ◽  
Gene Copy ◽  
Drosophila Pseudoobscura ◽  
A Site ◽  
Reduced Activity ◽  
Per Gene

A procedure is described for determining the mode and magnitude of gene-dosage compensation of transformed genes. It involves measurement of the ratio of the activity of a gene inserted at X-linked sites to the activity of the same gene inserted at autosomal sites. Applying the procedure to the Drosophila pseudoobscura Hsp82 gene inserted at ectopic sites in D. melanogaster and taking gene activity as proportional to the amount of transcript per gene copy, we conclude that (1) in both adults and larvae the gene is not compensated at autosomal sites or at a site in β-heterochromatin at the base of the X chromosome and is fully compensated at euchromatic X-chromosomal sites; (2) inappropriate normalization is responsible for a claim that the gene is compensated at autosomal sites; and (3) the observed compensation operates mainly or entirely by heightened activity of X-linked genes in males, rather than by reduced activity in females.

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