Showing papers on "Dosage compensation published in 2008"

X chromosome dosage compensation: how mammals keep the balance

Abstract: The development of genetic sex determination and cytologically distinct sex chromosomes leads to the potential problem of gene dosage imbalances between autosomes and sex chromosomes and also between males and females. To circumvent these imbalances, mammals have developed an elaborate system of dosage compensation that includes both upregulation and repression of the X chromosome. Recent advances have provided insights into the evolutionary history of how both the imprinted and random forms of X chromosome inactivation have come about. Furthermore, our understanding of the epigenetic switch at the X-inactivation center and the molecular aspects of chromosome-wide silencing has greatly improved recently. Here, we review various facets of the ever-expanding field of mammalian dosage compensation and discuss its evolutionary, developmental, and mechanistic components.

SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.

Abstract: X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation. Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.

X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations.

Abstract: X chromosome inactivation (XCI) is an essential mechanism for dosage compensation of X-linked genes in female cells. We report that subcultures from lines of female human embryonic stem cells (hESCs) exhibit variation (0–100%) for XCI markers, including XIST RNA expression and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on the inactive X chromosome (Xi). Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a monoallelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have already completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already not random. Moreover, XIST gene expression in subsets of cultured female hESCs is unstable and subject to stable epigenetic silencing by DNA methylation. In the absence of XIST expression, ≈12% of X-linked promoter CpG islands become hypomethylated and a portion of X-linked alleles on the Xi are reactivated. Because alterations in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine.

The chromosomal high-affinity binding sites for the Drosophila dosage compensation complex.

Abstract: Dosage compensation in male Drosophila relies on the X chromosome–specific recruitment of a chromatin-modifying machinery, the dosage compensation complex (DCC). The principles that assure selective targeting of the DCC are unknown. According to a prevalent model, X chromosome targeting is initiated by recruitment of the DCC core components, MSL1 and MSL2, to a limited number of so-called “high-affinity sites” (HAS). Only very few such sites are known at the DNA sequence level, which has precluded the definition of DCC targeting principles. Combining RNA interference against DCC subunits, limited crosslinking, and chromatin immunoprecipitation coupled to probing high-resolution DNA microarrays, we identified a set of 131 HAS for MSL1 and MSL2 and confirmed their properties by various means. The HAS sites are distributed all over the X chromosome and are functionally important, since the extent of dosage compensation of a given gene and its proximity to a HAS are positively correlated. The sites are mainly located on non-coding parts of genes and predominantly map to regions that are devoid of nucleosomes. In contrast, the bulk of DCC binding is in coding regions and is marked by histone H3K36 methylation. Within the HAS, repetitive DNA sequences mainly based on GA and CA dinucleotides are enriched. Interestingly, DCC subcomplexes bind a small number of autosomal locations with similar features.

Meiotic crossover number and distribution are regulated by a dosage compensation protein that resembles a condensin subunit

Abstract: Biological processes that function chromosome-wide are not well understood. Here, we show that the Caenorhabditis elegans protein DPY-28 controls two such processes, X-chromosome dosage compensation in somatic cells and meiotic crossover number and distribution in germ cells. DPY-28 resembles a subunit of condensin, a conserved complex required for chromosome compaction and segregation. In the soma, DPY-28 associates with the dosage compensation complex on hermaphrodite X chromosomes to repress transcript levels. In the germline, DPY-28 restricts crossovers. In many organisms, one crossover decreases the likelihood of another crossover nearby, an enigmatic process called crossover interference. In C. elegans, interference is complete: Only one crossover occurs per homolog pair. dpy-28 mutations increase crossovers, disrupt crossover interference, and alter crossover distribution. Early recombination intermediates (RAD-51 foci) increase concomitantly, suggesting that DPY-28 acts to limit double-strand breaks (DSBs). Reinforcing this view, dpy-28 mutations partially restore DSBs in mutants lacking HIM-17, a chromatin-associated protein required for DSB formation. Our work further links dosage compensation to condensin and establishes a new role for condensin components in regulating crossover number and distribution. We propose that both processes utilize a related mechanism involving changes in higher-order chromosome structure to achieve chromosome-wide effects.

The Genomic Distribution and Function of Histone Variant HTZ-1 during C. elegans Embryogenesis

Abstract: In all eukaryotes, histone variants are incorporated into a subset of nucleosomes to create functionally specialized regions of chromatin. One such variant, H2A.Z, replaces histone H2A and is required for development and viability in all animals tested to date. However, the function of H2A.Z in development remains unclear. Here, we use ChIP-chip, genetic mutation, RNAi, and immunofluorescence microscopy to interrogate the function of H2A.Z (HTZ-1) during embryogenesis in Caenorhabditis elegans, a key model of metazoan development. We find that HTZ-1 is expressed in every cell of the developing embryo and is essential for normal development. The sites of HTZ-1 incorporation during embryogenesis reveal a genome wrought by developmental processes. HTZ-1 is incorporated upstream of 23% of C. elegans genes. While these genes tend to be required for development and occupied by RNA polymerase II, HTZ-1 incorporation does not specify a stereotypic transcription program. The data also provide evidence for unexpectedly widespread independent regulation of genes within operons during development; in 37% of operons, HTZ-1 is incorporated upstream of internally encoded genes. Fewer sites of HTZ-1 incorporation occur on the X chromosome relative to autosomes, which our data suggest is due to a paucity of developmentally important genes on X, rather than a direct function for HTZ-1 in dosage compensation. Our experiments indicate that HTZ-1 functions in establishing or maintaining an essential chromatin state at promoters regulated dynamically during C. elegans embryogenesis.

The MSL3 chromodomain directs a key targeting step for dosage compensation of the Drosophila melanogaster X chromosome.

Abstract: The male-specific lethal (MSL) complex upregulates the single male X chromosome to achieve dosage compensation in Drosophila melanogaster. We have proposed that MSL recognition of specific entry sites on the X is followed by local targeting of active genes marked by histone H3 trimethylation (H3K36me3). Here we analyze the role of the MSL3 chromodomain in the second targeting step. Using ChIP-chip analysis, we find that MSL3 chromodomain mutants retain binding to chromatin entry sites but show a clear disruption in the full pattern of MSL targeting in vivo, consistent with a loss of spreading. Furthermore, when compared to wild type, chromodomain mutants lack preferential affinity for nucleosomes containing H3K36me3 in vitro. Our results support a model in which activating complexes, similarly to their silencing counterparts, use the nucleosomal binding specificity of their respective chromodomains to spread from initiation sites to flanking chromatin.

The status of dosage compensation in the multiple X chromosomes of the platypus.

Abstract: Dosage compensation has been thought to be a ubiquitous property of sex chromosomes that are represented differently in males and females. The expression of most X-borne genes is equalized between XX females and XY males in therian mammals (marsupials and “placentals”) by inactivating one X chromosome in female somatic cells. However, compensation seems not to be strictly required to equalize the expression of most Z-borne genes between ZZ male and ZW female birds. Whether dosage compensation operates in the third mammal lineage, the egg-laying monotremes, is of considerable interest, since the platypus has a complex sex chromosome system in which five X and five Y chromosomes share considerable genetic homology with the chicken ZW sex chromosome pair, but not with therian XY chromosomes. The assignment of genes to four platypus X chromosomes allowed us to examine X dosage compensation in this unique species. Quantitative PCR showed a range of compensation, but SNP analysis of several X-borne genes showed that both alleles are transcribed in a heterozygous female. Transcription of 14 BACs representing 19 X-borne genes was examined by RNA-FISH in female and male fibroblasts. An autosomal control gene was expressed from both alleles in nearly all nuclei, and four pseudoautosomal BACs were usually expressed from both alleles in male as well as female nuclei, showing that their Y loci are active. However, nine X-specific BACs were usually transcribed from only one allele. This suggests that while some genes on the platypus X are not dosage compensated, other genes do show some form of compensation via stochastic transcriptional inhibition, perhaps representing an ancestral system that evolved to be more tightly controlled in placental mammals such as human and mouse.

A Bird's-Eye View of Sex Chromosome Dosage Compensation

Abstract: Intensive study of a few genetically tractable species with XX/XY sex chromosomes has produced generalizations about the process of sex chromosome dosage compensation that do not fare well when applied to ZZ/ZW sex chromosome systems, such as those in birds. The inherent sexual imbalance in dose of sex chromosome genes has led to the evolution of sex-chromosome-wide mechanisms for balancing gene dosage between the sexes and relative to autosomal genes. Recent advances in our knowledge of avian genomes have led to a reexamination of sex-specific dosage compensation (SSDC) in birds, which is less effective than in known XX/XY systems. Insights about the mechanisms of SSDC in birds also suggest similarities to and differences from those in XX/XY species. Birds are thus offering new opportunities for studying dosage compensation in a ZZ/ZW system, which should shed light on the evolution of SSDC more broadly.

Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a

Abstract: Background X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males Chromosome silencing is triggered in cis by expression of the non-coding RNA Xist As such, correct regulation of the Xist gene promoter is required to establish appropriate X chromosome activity both in males and females Studies to date have demonstrated co-transcription of an antisense RNA Tsix and low-level sense transcription prior to onset of X inactivation The balance of sense and antisense RNA is important in determining the probability that a given Xist allele will be expressed, termed the X inactivation choice, when X inactivation commences

Characterization of the bovine pseudoautosomal boundary: Documenting the evolutionary history of mammalian sex chromosomes

Abstract: Maleness in placental mammals and marsupials is determined by the SRY gene located on the Y chromosome. This major sex determinant arose ∼166 million years ago (Mya) on an ancestral autosome as an allele of the SOX3 gene (Veyrunes et al. 2008). As is commonly observed for chromosomes carrying sex-determining genes (Ohno 1967), the Y has since undergone progressive degeneration, being reduced in present-day man to a mere 25 Mb of euchromatin harboring no more than 27 distinct protein-coding genes or gene families, appended with an approximately equal amount of dispensable heterochromatin (Skaletsky et al. 2003). These numbers are to be compared with the ∼155 Mb and 1100 genes of its ancestral partner, the X chromosome (Ross et al. 2005). The decay of the Y is thought to result from the successive selection of male-beneficial/female-deleterious alleles embedded in haplotypes that lost the ability to recombine with the X and are hence confined to males (Charlesworth 1991). Absence of recombination causes rapid degeneration by mutation, deletion, and transposon invasion accumulating as a result of a higher mutation rate in the male versus the female germline (due to the larger number of cell divisions required to produce male vs. female gametes), inefficient repair (e.g., Muller’s ratchet), and inefficient selection (e.g., shielding of deleterious recessives and Hill–Robertson interference) (e.g., Charlesworth et al. 2005; Bachtrog 2006; Graves 2006). The most commonly invoked recombination-blocking mechanism is chromosomal inversion. The observation of a stepwise increase in sequence similarity between genes ordered on the human X with their gametologs on the Y (“evolutionary strata”) suggests that five such recombination-blocking inversions have occurred in the human lineage (Lahn and Page 1999; Ross et al. 2005). These have isolated an increasing proportion of the Y from its X partner, progressively reducing the region of X–Y homology to the ∼2.7 Mb pseudoautosomal region 1 (PAR1). The five inversions in the human lineage were initially dated to 240–320 Mya, 130–170 Mya, 80–130 Mya, 38–44 Mya, and 29–32 Mya, respectively, yet recent reexamination of the age of the therian sex chromosomes (Veyrunes et al. 2008) forces reevaluation of these estimates. Loss of genes from the Y causes male hemizygosity and thus a different gonosome-to-autosome balance in the two sexes. This is thought to drive progression of dosage compensation involving (in mammals) doubling of expression levels from the X (Nguyen and Disteche 2006) and compensatory XIST-dependent inactivation of one X chromosome in females (Lyon 1961; Heard and Disteche 2006). Notably, while virtually all genes located in the older strata undergo X inactivation, their proportion decreases in the younger layers (Carrel and Willard 2005). Concomitantly, the enrichment in L1 interspersed repeats, which may operate as way stations spreading the inactivation process (Lyon 1998; Carrel et al. 2006), increases with stratum age (Ross et al. 2005). The generalization of dosage compensation across most of the X chromosome is thought to underlie its “frozen” gene content in mammals (Ohno 1967). The human and dog X chromosome sequences, for instance, are essentially colinear, while the human and mouse X chromosomes are nearly perfectly syntenic despite multiple intrachromosomal rearrangements (Ross et al. 2005). Figure 1A illustrates the equally remarkable conservation of gene content and order between the human and bovine X chromosomes. Figure 1. (A) Graphical representation of unique BLAST hits (E-value < 10−2) between the human and bovine X chromosomes. Sequences mapping to human PAR1-2 or strata 1–5 are color-labeled as indicated. (B) Schematic representation of distal ... Despite the largely frozen gene content of the X, the evolution of mammalian sex chromosomes has been punctuated by interchromosomal exchanges. An autosome to proto-gonosome translocation occurring after placental mammals diverged from marsupials has increased the size of the eutherian neo-gonosome by addition of the “X added region” (XAR) (Graves 2006). Autosome to Y transposition has augmented the content of the Y chromosome in male-beneficial genes, including retrotransposition of CDY before the divergence of marsupials and eutherians (Lahn and Page 1999; Skaletsky et al. 2003), transposition of DAZ during primate evolution (Saxena et al. 1996), and transposition of FLJ36031 prior to carnivore radiation and TETY1 following the divergence of cat and dog lineages (Murphy et al. 2006). Moreover, the human Y euchromosome has acquired an X transposed region (XTR) after its divergence from chimpanzees (Skaletsky et al. 2003). In addition, X-linked genes have generated pseudogenes by retrotransposition to autosomes, presumably to compensate for their silencing during male meiotic sex chromosome inactivation (MSCI) (e.g., Potrzebowski et al. 2008).

Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders

Abstract: In mammals females inactivate one of the two X chromosomes during early development to achieve an equal gene dosage between sexes. This process, named X chromosome inactivation (XCI), usually occurs randomly. However, in a few instances, non-random XCI may take place, thus modulating the phenotype observed in female patients carrying mutations in X-linked genes. Different aspects related to dosage compensation contribute to explain the influences of XCI on the phenotypic variability observed in female patients. The study of two X-linked dominant male-lethal disorders, such as the microphthalmia with linear skin lesions (MLS) syndrome and the oral-facial-digital type I (OFDI) syndrome, offers the opportunity to discuss this intriguing topic. In addition, recent data on the characterisation of a murine model for OFDI provide the opportunity to discuss how differences in the XCI between Homo sapiens and Mus musculus can justify the discrepancies between the phenotypes observed in OFDI patients and the corresponding murine model.

Incorporation of the noncoding roX RNAs alters the chromatin-binding specificity of the Drosophila MSL1/MSL2 complex.

Abstract: The male-specific lethal (MSL) protein-RNA complex is required for X chromosome dosage compensation in Drosophila melanogaster. The MSL2 and MSL1 proteins form a complex and are essential for X chromosome binding. In addition, the MSL complex must integrate at least one of the noncoding roX RNAs for normal X chromosome binding. Here we find the amino-terminal RING finger domain of MSL2 binds as a complex with MSL1 to the heterochromatic chromocenter and a few sites on the chromosome arms. This binding required the same amino-terminal basic motif of MSL1 previously shown to be essential for binding to high-affinity sites on the X chromosome. While the RING finger domain of MSL2 is sufficient to increase the expression of roX1 in females, activation of roX2 requires motifs in the carboxyl-terminal domain. Binding to hundreds of sites on the X chromosome and efficient incorporation of the roX RNAs into the MSL complex require proline-rich and basic motifs in the carboxyl-terminal domain of MSL2. We suggest that incorporation of the roX RNAs into the MSL complex alters the binding specificity of the chromatin-binding module formed by the amino-terminal domains of MSL1 and MSL2.

Muller's Ratchet and the Degeneration of Y Chromosomes: A Simulation Study

Abstract: A typical pattern in sex chromosome evolution is that Y chromosomes are small and have lost many of their genes. One mechanism that might explain the degeneration of Y chromosomes is Muller's ratchet, the perpetual stochastic loss of linkage groups carrying the fewest number of deleterious mutations. This process has been investigated theoretically mainly for asexual, haploid populations. Here, I construct a model of a sexual population where deleterious mutations arise on both X and Y chromosomes. Simulation results of this model demonstrate that mutations on the X chromosome can considerably slow down the ratchet. On the other hand, a lower mutation rate in females than in males, background selection, and the emergence of dosage compensation are expected to accelerate the process.

Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs.

Abstract: Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3' stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the "roX box," were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3' end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex.

Differential replication dynamics for large and small Vibrio chromosomes affect gene dosage, expression and location

Abstract: Replication of bacterial chromosomes increases copy numbers of genes located near origins of replication relative to genes located near termini. Such differential gene dosage depends on replication rate, doubling time and chromosome size. Although little explored, differential gene dosage may influence both gene expression and location. For vibrios, a diverse family of fast growing gammaproteobacteria, gene dosage may be particularly important as they harbor two chromosomes of different size. Here we examined replication dynamics and gene dosage effects for the separate chromosomes of three Vibrio species. We also investigated locations for specific gene types within the genome. The results showed consistently larger gene dosage differences for the large chromosome which also initiated replication long before the small. Accordingly, large chromosome gene expression levels were generally higher and showed an influence from gene dosage. This was reflected by a higher abundance of growth essential and growth contributing genes of which many locate near the origin of replication. In contrast, small chromosome gene expression levels were low and appeared independent of gene dosage. Also, species specific genes are highly abundant and an over-representation of genes involved in transcription could explain its gene dosage independent expression. Here we establish a link between replication dynamics and differential gene dosage on one hand and gene expression levels and the location of specific gene types on the other. For vibrios, this relationship appears connected to a polarisation of genetic content between its chromosomes, which may both contribute to and be enhanced by an improved adaptive capacity.

Expression of X-linked genes in deceased neonates and surviving cloned female piglets.

Abstract: Animal cloning through somatic cell nuclear transfer (NT) is very inefficient, probably due to insufficient reprogramming of the donor nuclei, which in turn would cause the dysregulation of gene expression. X-Chromosome inactivation (XCI) is a multi-step epigenetic process utilized by mammals to achieve dosage compensation in females. Our aim was to determine if any dysregulation of X-linked genes, which would be indicative of unfaithful reprogramming of donor nuclei, was present in cloned pigs. Real time reverse transcription polymerase chain reaction (RT-PCR) was performed to quantify the transcript levels of five X-linked genes, X inactivation-specific transcript (XIST), TSIX (the reverse spelling of XIST), hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1), glucose-6-phosphate dehydrogenase (G6PD), V-raf murine sarcoma 3,611 viral oncogene homolog 1 (ARAF1), and one autosomal gene, alpha-1 type IV collagen (COL4A1) in major organs of neonatal deceased and surviving female cloned pigs as well as their age-matched control pigs from conventional breeding. Aberrant expression level of these genes was prevalent in the neonatal deceased clones, while it was only moderate in cloned pigs that survived after birth. These results suggest a correlation between the viability of the clones and the normality of their gene expression and provide a possible explanation for the death of a large portion of cloned animals around birth.

Neo-sex chromosomes in the black muntjac recapitulate incipient evolution of mammalian sex chromosomes

Abstract: Background The regular mammalian X and Y chromosomes diverged from each other at least 166 to 148 million years ago, leaving few traces of their early evolution, including degeneration of the Y chromosome and evolution of dosage compensation.

Structure-function analysis of the RNA helicase maleless

Abstract: Loss of function of the RNA helicase maleless (MLE) in Drosophila melanogaster leads to male-specific lethality due to a failure of X chromosome dosage compensation. MLE is presumably involved in incorporating the non-coding roX RNA into the dosage compensation complex (DCC), which is an essential but poorly understood requirement for faithful targeting of the complex to the X chromosome. Sequence comparison predicts several RNA-binding domains in MLE but their properties have not been experimentally verified. We evaluated the RNA-binding characteristics of these conserved motifs and their contributions to RNA-stimulated ATPase activity, to helicase activity, as well as to the targeting of MLE to the nucleus and to the X chromosome territory. We find that RB2 is the dominant, conditional RNA-binding module, which is indispensable for ATPase and helicase activity whereas the N-terminal RB1 motif does not bind RNA, but is involved in targeting MLE to the X chromosome. The C-terminal domain containing a glycine-rich heptad repeat adds potential dimerization and RNA-binding surfaces which are not required for helicase activity.

The MLE subunit of the Drosophila MSL complex uses its ATPase activity for dosage compensation and its helicase activity for targeting.

Abstract: In Drosophila, dosage compensation—the equalization of most X-linked gene products between XY males and XX females—is mediated by the MSL complex that preferentially associates with numerous sites on the X chromosome in somatic cells of males, but not of females. The complex consists of a noncoding RNA and a core of five protein subunits that includes a histone acetyltransferase (MOF) and an ATP-dependent DEXH box RNA/DNA helicase (MLE). Both of these enzymatic activities are necessary for the spreading of the complex to its sites of action along the X chromosome. MLE is related to the ATPases present in complexes that remodel chromatin by altering the positioning or the architectural relationship between nucleosomes and DNA. In contrast to MLE, none of these enzymatic subunits has been shown to possess double-stranded nucleic acid-unwinding activity. We investigated the function of MLE in the process of dosage compensation by generating mutations that separate ATPase activity from duplex unwinding. We show that the ATPase activity is sufficient for MLE's role in transcriptional enhancement, while the helicase activity is necessary for the spreading of the complex along the X chromosome.

SU(VAR)3-7 Links Heterochromatin and Dosage Compensation in Drosophila

Abstract: In Drosophila, dosage compensation augments X chromosome-linked transcription in males relative to females. This process is achieved by the Dosage Compensation Complex (DCC), which associates specifically with the male X chromosome. We previously found that the morphology of this chromosome is sensitive to the amounts of the heterochromatin-associated protein SU(VAR)3-7. In this study, we examine the impact of change in levels of SU(VAR)3-7 on dosage compensation. We first demonstrate that the DCC makes the X chromosome a preferential target for heterochromatic markers. In addition, reduced or increased amounts of SU(VAR)3-7 result in redistribution of the DCC proteins MSL1 and MSL2, and of Histone 4 acetylation of lysine 16, indicating that a wild-type dose of SU(VAR)3-7 is required for X-restricted DCC targeting. SU(VAR)3-7 is also involved in the dosage compensated expression of the X-linked white gene. Finally, we show that absence of maternally provided SU(VAR)3-7 renders dosage compensation toxic in males, and that global amounts of heterochromatin affect viability of ectopic MSL2-expressing females. Taken together, these results bring to light a link between heterochromatin and dosage compensation.

Somatic sexual differentiation in Caenorhabditis elegans.

Abstract: The two sexes of the nematode Caenorhabditis elegans are the self-fertile hermaphrodite (essentially a female with a mixed germ line) and the male, and these differ extensively in anatomy, physiology, and behavior. At hatching, C. elegans larvae of each sex are nearly indistinguishable, differing mainly in the sex-specific death of a handful of neurons. After birth, however, a number of blast cells undergo radically different lineages and differentiation programs in the two sexes, leading to adults in which about one-third of cells are overtly dimorphic. The first C. elegans mutants causing discordance between genetic and phenotypic sex were isolated more than 30 years ago. Since then much progress has been made in uncovering the chromosomal elements and downstream regulatory pathways that control sex determination and sexual differentiation in the worm. The primary signal for sex determination is the ratio of X chromosomes to sets of autosomes, with hermaphrodites normally having two X chromosomes (XX) and males one (XO). The X:A signal is exquisitely dose-sensitive and operates via a group of X-linked regulators acting in opposition to a group of autosomal regulators that compete for the control of the master sex regulator xol-1. The activity of xol-1 coordinately regulates the formation of an active X chromosome dosage compensation complex and the activity of a sex determination regulatory cascade. The sex determination pathway globally controls all sexually dimorphic features by conferring sex specificity on downstream regulatory modules, largely via the action of TRA-1, a Ci/GLI family transcription factor with high activity in hermaphrodites and low activity in males. Much of this regulation involves the imposition of sex-specific activity on general developmental regulators in specific cell lineages. Recent work has answered long-standing questions about the molecular mechanisms controlling the sex determination pathway and shown that some C. elegans sexual regulators have counterparts regulating sexual development in other phyla.