male-specific lethal 2

DEVELOPMENTAL BIOLOGY

Embryonic

In embryonic nuclei, MSLs and monoacetylated histone H4 associate with the X chromosome. This was established using double fluorescent in situ hybridization with an X chromosome DNA probe and immunostaining for MSL protein. The late blastoderm/early gastrula are the earliest stages at which the MSLs are detected in the subnuclear localization pattern characteristic of male embryos. Earlier than this, MSLs are rather homogeneously distributed in the nucleus. It seems that MSLs become localized simultaneously, or over a very short period of time. MSL localization to the X chromosome without colocalization of monoacetylated H4 has been thought to suggest that MSLs localize prior to histone H4 (Franke, 1996).

Effects of Mutation or Deletion

There is no significant amount of embryonic death caused by msl-2 mutation, and no significant effect of msl-2 on viability of females or heterozygous males. Although most msl-2 males are killed in the larval stages, some do reach the prepupal stage. Mutants develop very slowly, most remaining in the third-instar stage for several days until dying as larvae or in the process of forming a puparium (Belote, 1980).

Msl-2 is required for the male-specific assembly of a dosage compensation regulatory complex on the X chromosome of Drosophila. Msl-2 binds in a reproducible, partial pattern to the male X chromosome in the absence of Mle or Msl-3, or when ectopically expressed at a low level in females. Moreover, the pattern of Msl-2 binding corresponds precisely in each case to that of MSL-1, suggesting that the two proteins function together to associate with the X chromosome. When MSL-1 function is compromised, Msl-2 is only localized to sites where the mutant form of MSL-1 is bound. Thus, a partial Msl-2 pattern is observed in msl-1 mutants. Likewise, when Msl-2 is present in limiting quantities, MSL-1 is precisely restricted to the sites of Msl-2 localization. Ectopic Msl-2 expression in females results in a dominant female phenotype. EMS-induced loss of function msl-1 and msl-2 alleles were isolated in a screen for suppressors of the toxic effects of Msl-2 expression in females. One such mutant lacks the RING finger motif. Site-directed mutagenesis was also used to determine the importance of the Msl-2 RING finger domain and second cysteine-rich motif. The mutations, including those in conserved zinc coordinating cysteines, confirm that the RING finger is essential for Msl-2 function, while suggesting a less stringent requirement for an intact second motif, the metalothionein-like cysteine cluster known as a PHD finger (Lyman, 1997).

The binding of each of the MSLs, and of histone H4 acetylated on lysine 16, to the X chromosome requires the presence of all four MSL proteins. For example, no association of the MSL-3 protein with the X chromosome is detected in msl-1 mutants. Throughout embryogenesis, in none of the homozygous male embryos mutant for msl-2 or msl-3 could association of the other MSL proteins or monoacetylated histone with the X chromosome be detected. msl-1 mutant embryos show association of MSL proteins with X chromosomes up to stage 9, while in mle mutants such association is seen up to stage 10, but this binding can be attributed to the presence of maternal MLE and MSL-1 (Franke, 1996).

In Drosophila, dosage compensation requires assembly of the Male Specific Lethal (MSL) protein complex for doubling transcription of most X-linked genes in males. The recognition of the X chromosome by the MSL complex has been suggested to include initial assembly at ~35 chromatin entry sites and subsequent spreading of mature complexes in cis to numerous additional sites along the chromosome. To understand this process further, MSL patterns were examined in a range of wild-type and mutant backgrounds producing different amounts of MSL components. The data support a model in which MSL complex binding to the X is directed by a hierarchy of target sites that display different affinities for the MSL proteins. Chromatin entry sites differ in their ability to provide local intensive binding of complexes to adjacent regions, and need high MSL complex titers to achieve this. A set of definite autosomal regions (~70), competent to associate with the functional MSL complex in wild-type males, was mapped. Overexpression of both MSL1 and MSL2 stabilizes this binding and results in inappropriate MSL binding to the chromocenter and the 4th chromosome. Thus, wild-type MSL complex titers are critical for correct targeting to the X chromosome (Demakova, 2003).

A functional dosage compensation complex required for male killing in Drosophila

Bacteria that selectively kill males ('male-killers') were first characterized more than 50 years ago in Drosophila and have proved to be common in insects. However, the mechanism by which sex specificity of virulence is achieved has remained unknown. This study tested the ability of Spiroplasma poulsonii to kill Drosophila melanogaster males carrying mutations in genes that encode the dosage compensation complex. The bacterium failed to kill males lacking any of the five protein components of the complex (Veneti, 2005).

Certain isofemale lines of Drosophila only give rise to daughters following the death of male embryos. Male death is due to the presence of intracellular bacteria that pass from a female to her progeny and that selectively kill males during embryogenesis. These male-killing bacteria are found in a wide range of other insect species, and many different bacteria have evolved male-killing phenotypes. In some host species, male-killers drive the host population sex ratio to levels as high as 100 females per male and alter the pattern of mate competition. However, the underlying processes that produce male-limited mortality are unclear. This study examined the interaction between the male-killing bacterium Spiroplasma poulsonii and the sex determination pathway of D. melanogaster (Veneti, 2005).

The primary signal of sex in Drosophila is the X-to-autosome ratio. This signal is permanently established in expression of Sex-lethal (Sxl) in females and its absence in males. This, in turn, effects three processes: germline sexual identity, somatic sexual differentiation, and dosage compensation, the process by which the gene expression titer on the X chromosome is equalized between two sexes despite their difference in X chromosome number. Mutations in the gene tra that convert XX individuals to male somatic sex do not induce female death. These observations indicate germline formation and migration happen correctly in male embryos and that dying male embryos do not express Sxl. Therefore, the requirement of the Spiroplasma for genes within the system of dosage compensation was examined (Veneti, 2005).

In Drosophila, the single X of males is hypertranscribed. This process of hypertranscription requires the formation of the dosage compensation complex (DCC) and its binding to (and modification of) the X chromosome. SXL in female Drosophila inhibits the production of MSL-2 protein, which is thus only present in male Drosophila. MSL-2 forms a complex with four other proteins, MSL-1, MSL-3, MLE, and MOF, which collectively form the DCC. MSL-1, MSL-3, MLE, and MOF are constitutively present in both males and females and are also supplied maternally. The complete DCC binds, with JIL-1, to the male X chromosome at various entry points, and, with the products of two noncoding RNAs, RoX1 and RoX2, it affects the modification of the single X chromosome and its hypertranscription (Veneti, 2005).

The effect was examined of mutations within the host DCC on the ability of the male-killer to function. The survival of male progeny beyond embryogenesis to L2/L3 (and in one case adult) was scored in the presence of different loss-of-function mutations within the dosage compensation system (normal male-killing occurs during embryogenesis), in the presence and absence of infection. Because many genes within this group additionally show strong maternal effects, the effect of mutations was in each case tested by using both mothers that were heterozygous for the loss-of-function mutation and mothers homozygous for it (Veneti, 2005).

Uninfected males homozygous for loss-of-function mutations within the dosage compensation system generally survive to the third larval instar. Survival to the third larval instar was studied for loss-of-function alleles of msl-1 (alleles msl-1¹ and msl-1^b), msl-2 (msl-2^g227 and msl-2^g134), msl-3 (msl-3¹³²), mle (mle⁹, mle¹), and mof (mof¹), and survival to adult for mle¹/mle⁶ transheterozygotes. In the case of all alleles of msl-1, msl-3, mle, and mof, a similar pattern is observed: Males homozygous or hemizygous for the loss-of-function mutation have appreciable survival in the presence of infection when their mother is also homozygous for the loss-of-function mutation. In contrast, heterozygous male embryos that were siblings of the above (that will have a wild-type DCC) were always killed, as were all male embryos in the case where the mother was heterozygous (where maternal supply of these proteins enables dosage compensation to be initiated, although not maintained). In the case of mle¹/mle⁶ transheterozygotes, male survival to adult was observed. For the case of mof, male-killing was restored to full efficiency when 18H1, a transgenic copy of mof, was added to the mof¹ loss-of-function background. Within the above crosses, three observations make sure the observation that Spiroplasma was fully operational. First, crosses involving heterozygous mothers, where male-killing was complete, were conducted concurrently with those using homozygous mothers, and the females in these crosses were siblings from the same vials. Second, in each cross and vial where homozygous males survived, heterozygous males (with wild-type function) still died. Finally, F₁ females derived from these crosses, when mated to wild-type males, produced a full, female-biased sex ratio (Veneti, 2005).

In the case of msl-2, where there is no maternal supply of MSL-2, survival of homozygous sons was observed for both homozygous and heterozygous mothers for the case of the mutation msl-2^g134. For the case of msl-2 ^g227, no male progeny were observed from infected females (table S5). This mutation does not rescue males in the assay, probably because the two mutations have different effects on msl-2 expression. The msl-2^g134 allele prevents formation of MSL-2 protein, whereas msl-2 ^g227 potentially encodes the RING-finger element of a truncated MSL-2 protein (Veneti, 2005).

Thus, absence or reduced function of any of the proteins of the DCC can reduce the efficiency of male killing, and a functional DCC is required for male killing by S. poulsonii. The fact that the genes mediating this process in Drosophila have been well studied can be exploited to yield further insights into the mechanism of male killing (Veneti, 2005).

X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila

The evolution of sex chromosomes has resulted in numerous species in which females inherit two X chromosomes but males have a single X, thus requiring dosage compensation. MSL (Male-specific lethal) complex increases transcription on the single X chromosome of Drosophila males to equalize expression of X-linked genes between the sexes. The biochemical mechanisms used for dosage compensation must function over a wide dynamic range of transcription levels and differential expression patterns. It has been proposed that the MSL complex regulates transcriptional elongation to control dosage compensation, a model subsequently supported by mapping of the MSL complex and MSL-dependent histone 4 lysine 16 acetylation to the bodies of X-linked genes in males, with a bias towards 3' ends. However, experimental analysis of MSL function at the mechanistic level has been challenging owing to the small magnitude of the chromosome-wide effect and the lack of an in vitro system for biochemical analysis. This study used global run-on sequencing (GRO-seq) to examine the specific effect of the MSL complex on RNA Polymerase II (RNAP II) on a genome-wide level. Results indicate that the MSL complex enhances transcription by facilitating the progression of RNAP II across the bodies of active X-linked genes. Improving transcriptional output downstream of typical gene-specific controls may explain how dosage compensation can be imposed on the diverse set of genes along an entire chromosome (Larschan, 2011).

To investigate how the MSL complex specifically increases transcription of X-linked genes, GRO-seq was performed in SL2 cells, a male Drosophila cell line that has been extensively characterized for MSL function. To show the average enrichment across genes, a 3-kb 'metagene' profile was plotted in which the internal regions were rescaled so that all genes appear to have the same length. Analysis was restricted to expressed genes that were sufficiently large (>2.5 kb) so that gene-body effects could be clearly assessed (822 X-linked genes, 3,420 autosomal genes), and all gene profiles were normalized by their copy number as determined by analysis of SL2 DNA content. High correlation coefficients were observed between replicate libraries. The metagene profiles revealed a prominent 5' peak of paused RNAP II consistent with previous chromatin immunoprecipitation (ChIP) and analysis of short 5' RNAs. In addition, a peak of RNAP II density downstream of the metagene 3' processing site is evident, possibly due to slow release in regions of transcription termination. The 3' peak is present even when the influence of neighbouring gene transcription is eliminated (Larschan, 2011).

The central question with regard to dosage compensation is how genes on the X chromosome differ on average from genes on autosomes. Overall, it was found that RNAP II density on active X-linked genes was higher than on autosomal genes, specifically over gene bodies. The increase in tag density over the bodies of X-linked genes compared to autosomal genes was approximately 1.4-fold, consistent with previous estimates of MSL-dependent dosage compensation. RNAP II ChIP was performed in SL2 cells, confirming higher occupancy on X-linked genes compared to autosomes but with lower resolution and reduced sensitivity. Therefore, GRO-seq was performed to analyse X and autosomal differences (Larschan, 2011).

To measure how X and autosomes differed on average in the distribution of elongating RNAP II, genes were segmented into their 5' 500 bp and the remainder of the coding region. The remainder of the coding region was subdivided further into 5' and 3' segments (25% and 75%, respectively). Using this segmentation, RNAP II pausing and elongation were quantitated separately on the basis of the unscaled GRO-seq signal. The pausing index (PI) was previously defined as the ratio of the GRO-seq signal at the 5' peak to the average signal over gene bodies. Herewe calculated the PI was calculated for X and autosomal genes as the ratio of the 5' peak to the first 25% of the remaining gene body, and no statistically significant difference was found when the two groups were compared (Larschan, 2011).

To examine separately transcription elongation across gene bodies, the elongation density index (EdI) was defined as the ratio of tag density in the 3' region of each gene compared to its 5' region after the first 500 bp. In contrast to the analysis of 5' pausing, statistically significant differences was found in EdI between X and autosomes. This conclusion was robust to how the 5' and 3' regions of genes were divided. As defined, the average PI (log scale) is a positive number because RNAP II is generally enriched at 5' ends compared to gene bodies; the average EdI (log scale) is a negative number, as the relative density of RNAP II typically decreases from the beginning to the end of gene bodies. It is concluded that X-linked genes, on average, show a significantly smaller decrease in RNAP II density along their gene bodies when compared to autosomal genes (Larschan, 2011).

To measure the specific contribution of the MSL complex to the increase in RNAP II within X-linked gene bodies, MSL2 RNA interference (RNAi) was used to reduce complex levels in male SL2 cells. Excellent correlations between replicate data sets were observed. To confirm the X-specific effect of MSL2 RNAi, the distributions of the GRO-seq signal (averaged over the bodies of genes excluding the 5' peak) were computed for all genes before and after RNAi. When comparing X versus autosomes, a preferential decrease was found on the X chromosome, with an average control:MSL RNAi ratio of 1.4. MSL-dependent changes in average GRO-seq density showed a weak but statistically significant correlation with changes in steady-state messenger RNA levels assayed by expression array or mRNA-Seq10. These results confirm that MSL-dependent changes in steady-state RNA levels reflect differences in active transcription on the X chromosome (Larschan, 2011).

In addition to assessing the average decrease of X-linked RNAP II density after MSL2 RNAi, it was asked whether any genes showed strong MSL-dependence, a hallmark of the roX genes that encode RNA components of the complex. It was found that roX2 showed a strong loss in GRO-seq density (ninefold) after MSL2 RNAi, as predicted. Interestingly, in the untreated or control RNAi samples, there is a prominent GRO-seq peak downstream of the major roX2 3' end, coincident with an MSL recruitment site. roX1 expression is low in this isolate of SL2 cells, and no other expressed genes on X or autosomes showed strong MSL dependence in these assays (Larschan, 2011).

Next the average RNAP II density was compared along X and autosomal metagene profiles after control and MSL2 RNAi. Unlike the initial analysis of X and autosomes, where different gene populations were compared, here it was possible to examine the same genes in the presence and absence of the MSL complex. It was found that after MSL2 RNAi, the density of elongating RNAP II over the bodies of X-linked genes decreased, approaching the level on autosomes. The presence of the MSL complex affected RNAP II density starting just downstream of the 5' peak and continuing through the bodies of X-linked genes. Thus, GRO-seq functional data correlate with physical association of the MSL complex, which is biased towards the 3' ends of active genes on the male X chromosome (Larschan, 2011).

To quantify the differences in density of engaged RNAP II in the presence and absence of the MSL complex, the PI and EdI were calculated for each gene, followed by the PI and EdI ratios comparing MSL2 and control RNAi treatment. It was found that both X and autosomes increased PI and decreased EdI after MSL2 RNAi treatment. However, in each case the change was larger on X than on autosomes, and the most profound difference was an MSL-dependent change in EdI on X compared with autosomes. EdI was computed, as before, by defining the 5' and 3' regions as 25% and 75%, respectively, of the gene body after removing the 5' peak, but the difference was statistically significant for all other values until the 3' end was reached. When these analyses were performed separately for two independently prepared sets of GRO-seq libraries, the results were also statistically significant. It is concluded that the MSL complex causes the transcriptional elongation profiles of X-linked genes to differ from those of autosomal genes (Larschan, 2011).

To visualize the location along gene bodies at which the MSL complex functions, control:MSL2 RNAi GRO-seq ratios were calculated and a metagene profile was generated. Here, values above zero represent higher relative amounts of engaged RNAP II in the presence of the MSL complex compared to after RNAi treatment. In contrast, values below zero represent a relative increase in engaged RNAP II after MSL2 RNAi. In the absence of the MSL complex, there is a relative increase in the amount of RNAP II localized to the 5' ends of both autosomal and X-linked genes, perhaps due to relocalization of RNAP II from the bodies of X-linked genes. A limitation of the GRO-seq assay is that it is not possible to distinguish between initiating and 5' paused polymerase, so a definitive role cannot be assigned for this 5' increase in RNAP II after MSL2 RNAi treatment. However, relative RNAP II levels over autosomal gene bodies do not increase, indicating that any relocalized enzyme in this experiment is likely to remain paused rather than progressing across transcription units. This is consistent with a model in which the functional outcome of MSL2 RNAi is to shift RNAP II density away from productive transcription through X-linked gene bodies (Larschan, 2011).

The local effect of the MSL complex was plotted to compare it to the status of histone 4 lysine 16 (H4K16) acetylation catalysed by the MOF component of the MSL complex. H4K16 acetylation typically is enriched at the 5' ends of most active genes in mammals and flies; in contrast, a 3' bias of this mark is a distinctive characteristic of the dosage compensated male X chromosome in Drosophila. Interestingly, there is an overall coincidence across gene bodies between the MSL-complex-dependent GRO-seq signal and the presence of H4K16 acetylation. How might H4K16 acetylation biased towards the 3' end of genes generate the improved transcriptional elongation indicated by the GRO-seq results? During transcription elongation, nucleosomes are thought to comprise a barrier to the progress of RNAP II and several well-studied elongation factors, including Spt6 and the FACT complex, are proposed to function by removing nucleosomes that block RNAP II progression and replacing them in the wake of transcription. Interestingly, H4K16 acetylation of nucleosomes has been observed to act in opposition to the formation of higher-order chromatin structure in vitro. Thus, H4K16 acetylation is likely to reduce further the steric hindrance to RNAP II progression through chromatin. Improving the entry of RNAP II into the bodies of genes may allow 5', gene-specific events to proceed at an increased but still regulated rate. Furthermore, reduction in the repressive effect of nucleosomes could increase mRNA output by improving the processivity of RNAP II on each template. Available methodologies cannot distinguish between these mechanisms in vivo, and therefore future approaches will be required to assess their relative contributions to dosage compensation (Larschan, 2011).

In addition to increasing the transcription of X-linked genes for dosage compensation, the MSL complex also positively regulates the roX noncoding RNA components of the complex, to promote their male specificity. roX1 expression is low in the SL2 cell line, but GRO-seq data indicate that active transcription of roX2 is highly dependent on MSL2 as predicted. Interestingly, there is a strong GRO-seq peak at the 3' roX2 DHS (DNaseI hypersensitive site), which contains sequences important for targeting the MSL complex to the X chromosome. Sites of roX gene transcription are thought to be critical for MSL complex assembly. Therefore, it is possible that paused RNAP II at the roX2 DHS could promote an open chromatin structure that facilitates MSL complex targeting or incorporation of noncoding roX2 RNA into the complex (Larschan, 2011).

In summary, it is proposed that the MSL complex functions on the male X chromosome to promote progression and processivity of RNAP II through the nucleosomal template. Improving transcriptional output downstream of typical gene-specific regulation makes biological sense when compensating the diverse set of genes found along an entire chromosome (Larschan, 2011).

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date revised: 10 December 2024

 

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