Caenorhabditis elegans Dosage Compensation Regulates Histone H4 Chromatin State on X Chromosomes

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.

Download Full-text

Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila

Life Science Alliance ◽

10.26508/lsa.202000996 ◽

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.

Download Full-text

Identification of X chromosome regions in Caenorhabditis elegans that contain sex-determination signal elements.

Genetics ◽

10.1093/genetics/138.4.1105 ◽

1994 ◽

Vol 138 (4) ◽

pp. 1105-1125

Author(s):

C C Akerib ◽

B J Meyer

Keyword(s):

Caenorhabditis Elegans ◽

Sex Determination ◽

X Chromosome ◽

Dosage Compensation ◽

X Chromosomes ◽

Sensitive Region ◽

Signal Element ◽

Number Of Genes ◽

Mutant Phenotypes ◽

Chromosome Regions

Abstract The primary sex-determination signal of Caenorhabditis elegans is the ratio of X chromosomes to sets of autosomes (X/A ratio). This signal coordinately controls both sex determination and X chromosome dosage compensation. To delineate regions of X that contain counted signal elements, we examined the effect on the X/A ratio of changing the dose of specific regions of X, using duplications in XO animals and deficiencies in XX animals. Based on the mutant phenotypes of genes that are controlled by the signal, we expected that increases (in males) or decreases (in hermaphrodites) in the dose of X chromosome elements could cause sex-specific lethality. We isolated duplications and deficiencies of specific X chromosome regions, using strategies that would permit their recovery regardless of whether they affect the signal. We identified a dose-sensitive region at the left end of X that contains X chromosome signal elements. XX hermaphrodites with only one dose of this region have sex determination and dosage compensation defects, and XO males with two doses are more severely affected and die. The hermaphrodite defects are suppressed by a downstream mutation that forces all animals into the XX mode of sex determination and dosage compensation. The male lethality is suppressed by mutations that force all animals into the XO mode of both processes. We were able to subdivide this region into three smaller regions, each of which contains at least one signal element. We propose that the X chromosome component of the sex-determination signal is the dose of a relatively small number of genes.

Download Full-text

The Caenorhabditis elegans Dosage Compensation Machinery Is Recruited to X Chromosome DNA Attached to an Autosome

Genetics ◽

10.1093/genetics/156.4.1603 ◽

2000 ◽

Vol 156 (4) ◽

pp. 1603-1621

Author(s):

Jason D Lieb ◽

Carlos Ortiz de Solorzano ◽

Enrique Garcia Rodriguez ◽

Arthur Jones ◽

Michael Angelo ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

X Chromosome ◽

Dosage Compensation ◽

Dna Sequences ◽

Three Dimensional ◽

Dosage Compensation Complex ◽

X Chromosomes ◽

Cis Acting ◽

Recognition Elements ◽

The Right

Abstract The dosage compensation machinery of Caenorhabditis elegans is targeted specifically to the X chromosomes of hermaphrodites (XX) to reduce gene expression by half. Many of the trans-acting factors that direct the dosage compensation machinery to X have been identified, but none of the proposed cis-acting X chromosome-recognition elements needed to recruit dosage compensation components have been found. To study X chromosome recognition, we explored whether portions of an X chromosome attached to an autosome are competent to bind the C. elegans dosage compensation complex (DCC). To do so, we devised a three-dimensional in situ approach that allowed us to compare the volume, position, and number of chromosomal and subchromosomal bodies bound by the dosage compensation machinery in wild-type XX nuclei and XX nuclei carrying an X duplication. The dosage compensation complex was found to associate with a duplication of the right 30% of X, but the complex did not spread onto adjacent autosomal sequences. This result indicates that all the information required to specify X chromosome identity resides on the duplication and that the dosage compensation machinery can localize to a site distinct from the full-length hermaphrodite X chromosome. In contrast, smaller duplications of other regions of X appeared to not support localization of the DCC. In a separate effort to identify cis-acting X recognition elements, we used a computational approach to analyze genomic DNA sequences for the presence of short motifs that were abundant and overrepresented on X relative to autosomes. Fourteen families of X-enriched motifs were discovered and mapped onto the X chromosome.

Download Full-text

Two Classes of Dosage Compensation Complex Binding Elements along Caenorhabditis elegans X Chromosomes

Molecular and Cellular Biology ◽

10.1128/mcb.01448-08 ◽

2009 ◽

Vol 29 (8) ◽

pp. 2023-2031 ◽

Cited By ~ 6

Author(s):

Timothy A. Blauwkamp ◽

Gyorgyi Csankovszki

Keyword(s):

Caenorhabditis Elegans ◽

X Chromosome ◽

Dosage Compensation ◽

Gene Products ◽

Dosage Compensation Complex ◽

X Chromosomes ◽

Linked Gene ◽

Unknown Mechanism

ABSTRACT Dosage compensation equalizes X-linked gene products between the sexes. In Caenorhabditis elegans, the dosage compensation complex (DCC) binds both X chromosomes in XX animals and halves the transcription from each. The DCC is recruited to the X chromosomes by a number of loci, rex sites, and is thought to spread from these sites by an unknown mechanism to cover the rest of the chromosome. Here we describe a novel class of DCC-binding elements that we propose serve as “way stations” for DCC binding and spreading. Both rex sites and way stations comprise strong foci of DCC binding on the native X chromosome. However, rex sites maintain their ability to bind large amounts of DCC even on X duplications detached from the native X, while way stations do not. These results suggest that two distinct classes of DCC-binding elements facilitate recruitment and spreading of the DCC along the X chromosome.

Download Full-text

SUMOylation is essential for sex-specific assembly and function of the Caenorhabditis elegans dosage compensation complex on X chromosomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1315793110 ◽

2013 ◽

Vol 110 (40) ◽

pp. E3810-E3819 ◽

Cited By ~ 16

Author(s):

R. R. Pferdehirt ◽

B. J. Meyer

Keyword(s):

Caenorhabditis Elegans ◽

Dosage Compensation ◽

Dosage Compensation Complex ◽

X Chromosomes ◽

And Function

Download Full-text

Sex determination in polyploids of Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/137.2.467 ◽

1994 ◽

Vol 137 (2) ◽

pp. 467-481

Author(s):

P M Meneely

Keyword(s):

Caenorhabditis Elegans ◽

Sex Determination ◽

X Chromosome ◽

Dosage Compensation ◽

Dna Sequences ◽

Maternal Effect ◽

Indirect Evidence ◽

Sex Reversal ◽

Diploid Males ◽

X Chromosomes

Abstract In Caenorhabditis elegans triploid animals with two X chromosomes (symbolized 3A;2X) are males. However, these triploid males can be feminized by making them mutant for recessive dosage compensation mutations, by adding X chromosome duplications or by microinjecting particular DNA sequences termed feminizing elements. None of these treatments affects diploid males. This study explores several aspects of these treatments in polyploids. The dosage compensation mutants exhibit a strong maternal effect, such that reduction of any of the dosage compensation gene functions in the mother leads to sex reversal of 3A;2X animals. Likewise, all X chromosome duplications tested cause both sex reversal and intersexual development of many 3A;2X animals. Microinjected feminizing element DNA does not cause extensive sex reversal, but does result in intersexual development in 3A;2X animals. Neither X chromosome duplications nor microinjected feminizing elements show that extreme maternal effect of the dosage compensation mutants, although there is indirect evidence for a maternal effect of the feminizing elements. In particular, very little feminizing element DNA needs to be microinjected in order to feminize triploid males, far less than what is needed for stable inheritance, implying that feminizing elements can work within the mother's gonad. However, even very high concentrations of microinjected feminizing elements do not affect sex determination in diploid males, suggesting that they are not part of the numerator of the X/A ratio. In addition, no pair of X chromosome duplications feminizes diploid males, suggesting that none of these duplications contains a numerator of the X/A ratio. Instead, I infer that an X-linked locus, as yet undefined, must be present in two copies for hermaphrodite development to ensue or that the two X chromosomes might interact.

Download Full-text

Bisection of the X chromosome disrupts the initiation of chromosome silencing during meiosis in Caenorhabditis elegans

Nature Communications ◽

10.1038/s41467-021-24815-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yisrael Rappaport ◽

Hanna Achache ◽

Roni Falk ◽

Omer Murik ◽

Oren Ram ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Rna Polymerase Ii ◽

X Chromosome ◽

Sex Chromosomes ◽

Sex Chromosome ◽

Transcription Analysis ◽

X Chromosomes ◽

Unique Character ◽

Active Transcription ◽

Heterogametic Sex

AbstractDuring meiosis, gene expression is silenced in aberrantly unsynapsed chromatin and in heterogametic sex chromosomes. Initiation of sex chromosome silencing is disrupted in meiocytes with sex chromosome-autosome translocations. To determine whether this is due to aberrant synapsis or loss of continuity of sex chromosomes, we engineered Caenorhabditis elegans nematodes with non-translocated, bisected X chromosomes. In early meiocytes of mutant males and hermaphrodites, X segments are enriched with euchromatin assembly markers and active RNA polymerase II staining, indicating active transcription. Analysis of RNA-seq data showed that genes from the X chromosome are upregulated in gonads of mutant worms. Contrary to previous models, which predicted that any unsynapsed chromatin is silenced during meiosis, our data indicate that unsynapsed X segments are transcribed. Therefore, our results suggest that sex chromosome chromatin has a unique character that facilitates its meiotic expression when its continuity is lost, regardless of whether or not it is synapsed.

Download Full-text

DOSAGE COMPENSATION IN DROSOPHILA MELANOGASTER TRIPLOIDS. II. GLUCOSE-6-PHOSPHATE DEHYDROGENASE ACTIVITY

Genetics ◽

10.1093/genetics/74.2.331 ◽

1973 ◽

Vol 74 (2) ◽

pp. 331-342

Author(s):

Gustavo Maroni ◽

Walter Plaut

Keyword(s):

Enzyme Activity ◽

Dosage Compensation ◽

Live Weight ◽

Regulatory Mechanisms ◽

Special Device ◽

Regulatory Factor ◽

X Chromosomes ◽

Integral Number ◽

Level Of Activity ◽

Glucose 6 Phosphate Dehydrogenase

ABSTRACT The level of activity of the enzyme glucose-6-phosphate dehydrogenase was determinel in flies having seven different chromosomic constitutions. All those having an integral number of chromosomes [XAA, XXAA, XAAA, XXAAA, and XXXAAA (X=X chromosome, A=set of autosomes)] were found to have similar units of enzyme activity/mg live weight, while diploid females with a duplication and triploid females with a deficiency showed dosage effect. The amount of enzyme activity per cell, on the other hand, is also independent of the number of X's present but appears roughly proportional to the number of sets of autosomes.—It is proposed that dosage-compensated sex-linked genes are controlled by a positively acting regulatory factor(s) of autosomal origin. With this hypothesis it is possible to explain dosage compensation as a consequence of general regulatory mechanisms without invoking a special device which applies only to the X chromosomes.

Download Full-text

Major sex-determining genes and the control of sexual dimorphism in Caenorhabditis elegans

Genome ◽

10.1139/g89-116 ◽

1989 ◽

Vol 31 (2) ◽

pp. 625-637 ◽

Cited By ~ 4

Author(s):

Jonathan Hodgkin ◽

Andrew D. Chisholm ◽

Michael M. Shen

Keyword(s):

Caenorhabditis Elegans ◽

Sex Determination ◽

X Chromosome ◽

Germ Line ◽

Cell Lineage ◽

Regulatory Genes ◽

Nematode Caenorhabditis Elegans ◽

X Chromosomes ◽

The Many ◽

Lineage Analysis

Sex determination in Caenorhabditis elegans involves a cascade of major regulatory genes connecting the primary sex determining signal, X chromosome dosage, to key switch genes, which in turn direct development along either male or female pathways. Animals with one X chromosome (XO) are male, while animals with two X chromosomes (XX) are hermaphrodite: hermaphrodite development occurs because the action of the regulatory genes is modified in the germ line so that both sperm and oocytes are made inside a completely female soma. The regulatory genes are being examined by both genetic and molecular means. We discuss how these major genes, in particular the last switch gene in the cascade, tra-1, might regulate the many different sex-specific events that occur during the development of the hermaphrodite and of the male.Key words: nematode, Caenorhabditis elegans, sex determination, sexual differentiation, cell lineage analysis.

Download Full-text