Expression of Msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila

Kelley, R. L.; Solovyeva, Irina; Lyman, L. M.; Richman, Robert A.; Solovyev, Victor; Kuroda, Mitzi I.

doi:10.1016/0092-8674(95)90007-1

Cited by 292 publications

(305 citation statements)

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“…The compensation of the X-linked gene runt appears to be under the direct control of the Sxl gene and does not involve the MSL complex (22). As expected, since Sxl makes a functional product only in females, equal levels of runt expression in the two sexes may be achieved by reducing (halving) the expression of the two doses of the gene in females (34). These considerations are fully concordant with the absence of H4Ac16 on runt nucleosomes.…”

Section: Global Histone Acetylation Is Required For the Spreading Of supporting

confidence: 64%

Linking Global Histone Acetylation to the Transcription Enhancement of X-chromosomal Genes in Drosophila Males

Smith¹,

Allis²,

Lucchesi³

2001

Journal of Biological Chemistry

148

150

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It has become well established for several genes that targeting of histone acetylation to promoters is required for the activation of transcription. In contrast, global patterns of acetylation have not been ascribed to any particular regulatory function. In Drosophila, a specific modification of H4, acetylation at lysine 16, is enriched at hundreds of sites on the male X chromosome due to the activity of the male-specific lethal (MSL) dosage compensation complex. Utilizing chromatin immunoprecipitation, we have determined that H4Ac16 is present along the entire length of X-linked genes targeted by the MSL complex with relatively modest levels of acetylation at the promoter regions and high levels in the middle and/or 3 end of the transcription units. We propose that global acetylation by the MSL complex increases the expression of X-linked genes by facilitating transcription elongation rather than by enhancing promoter accessibility. We have also determined that H4Ac16 is absent from a region of the X chromosome that includes a gene known to be dosage-compensated by a MSL-independent mechanism. This study represents the first biochemical interpretation of the very large body of cytological observations on the chromosomal distribution of the MSL complex.Many post-translational modifications of the highly conserved histone N-terminal tails are linked to transcriptional regulation (1), with the most widely studied modification being acetylation of histones H3 and H4. Genetic and biochemical data have demonstrated that histone acetyltransferases such as yGcn5p and yEsa1p are recruited to the promoters of specific genes for the activation of transcription (2-6). Loss of function mutations of the genes encoding these enzymes, however, reveal that they are also responsible for a broad pattern of acetylation with relatively modest effects on the level of transcription (2, 4, 6).In Drosophila, evidence for special roles for particular histone modifications was revealed with antisera to specific isoforms of H4. While H4 isoforms acetylated at lysine 5 or 8 are associated with numerous sites throughout the genome, H4 acetylated at lysine 12 is enriched in chromocentric heterochromatin, and H4 acetylated at lysine 16 (H4Ac16) is exclusively associated with the male X chromosome (7, 8). Male-specific acetylation of H4 at lysine 16 is mediated by males absent on the first (MOF), 1 a MYST-family histone acetyltransferase present in the male-specific lethal (MSL) complex (9 -11). This histone acetyltransferase-containing complex is responsible for the dosage compensation of many X-linked genes by increasing their transcription in males to achieve a level of gene product equivalent to that generated by the two X chromosomes in females. In addition to its protein subunits, the MSL complex contains one of two nontranslated RNAs, roX1 and roX2 (11-15). Current models suggest that functional complexes form at the sites of transcription of these RNAs, then access the X chromosome at a small number of additional entry sites and subseq...

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Section: Global Histone Acetylation Is Required For the Spreading Of supporting

confidence: 64%

Linking Global Histone Acetylation to the Transcription Enhancement of X-chromosomal Genes in Drosophila Males

Smith¹,

Allis²,

Lucchesi³

2001

Journal of Biological Chemistry

148

150

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“…This is based on the observation that Sex lethal (SXL) directs compensation of the runt (run) gene, but not through the action of the MSL proteins (Gergen 1987;Bernstein and Cline 1994). The discovery that transcripts with multiple SXL-binding sites were almost exclusively X-linked strengthened the idea of a female component of compensation acting by SXL repression of translation (Kelley et al 1995). Intriguingly, run is one of the X-linked genes with SXL-binding sites.…”

Section: Discussionmentioning

confidence: 92%

roXRNAs Are Required for Increased Expression of X-Linked Genes inDrosophila melanogasterMales

Deng

Meller

2006

Genetics

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The male-specific lethal (MSL) ribonucleoprotein complex is necessary for equalization of X:A expression levels in Drosophila males, which have a single X chromosome. It binds selectively to the male X chromosome and directs acetylation of histone H4 at lysine 16 (H4Ac16), a modification linked to elevated transcription. roX1 and roX2 noncoding RNAs are essential but redundant components of this complex. Simultaneous removal of both roX RNAs reduces X localization of the MSL proteins and permits their ectopic binding to autosomal sites and the chromocenter. However, the MSL proteins still colocalize, and low levels of H4Ac16 are detected at ectopic sites of MSL binding and residual sites on the X chromosome of roX1 À roX2 À males. Microarray analysis was performed to reveal the effect of roX1 and roX2 elimination on X-linked and autosomal gene expression. Expression of the X chromosome is decreased by 26% in roX1 À roX2 À male larvae. Enhanced expression could not be detected at autosomal sites of MSL binding in roX1 À roX2 À males. These results implicate failure to compensate X-linked genes, rather than inappropriate upregulation of autosomal genes at ectopic sites of MSL binding, as the primary cause of male lethality upon loss of roX RNAs.

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“…Splicing is an essential process that allows removal of intronic sequences from mRNA precursors (pre-mRNA)+ Introns are defined by short conserved sequences (GU at the 59 and AG at 39 end of the major class of introns) and more degenerate adjacent consensus sequences (reviewed by Burge et al+, 1999)+ The 39 splice site AG, for example, is preceded by a pyrimidine-rich stretch (Py-tract) and a branch point sequence further upstream+ Recognition of these sequences triggers the assembly of a large macromolecular complex-the spliceosome-composed of five small nuclear ribonucleoprotein (snRNP) particles and 50 to 100 non-snRNP polypeptides, that is responsible for the biochemical reactions leading to intron removal (reviewed by Krämer, 1996;Kambach et al+, 1999)+ Spliceosome assembly involves several distinct steps, at least in vitro (reviewed by Reed, 2000)+ The earliest steps include, in higher eukaryotes, interactions between U1 snRNP and the 59 splice site, of the U2 auxiliary factor (U2AF) 65-and 35-kDa subunits with the Py-tract and 39 ss AG, respectively, and of SF1/ mammalian branchpoint binding protein (mBBP) with the branchpoint (Zhuang & Weiner, 1986;Zamore et al+, 1992;Berglund et al+, 1997;Merendino et al+, 1999;Wu et al+, 1999;Zorio & Blumenthal, 1999)+ Other factors influence formation of this complex in a substratespecific manner+ The early (E) complex commits premRNAs to be spliced and is ATP independent+ E complex precedes formation of the ATP-dependent prespliceosomal complex (also known as complex A), that contains U2 snRNP stably associated with the branchpoint and surrounding sequences+ Incorporation of the U4/5/6 tri-snRNP results in fully assembled spliceosomes that can exist in two conformations (complexes B and C), of which complex C is the catalytically active form (reviewed by Staley & Guthrie, 1998)+ Intronic sequences can sometimes be retained in a regulated fashion in particular mRNAs+ For instance, several families of RNA and DNA viruses transcribe intronic sequences that in the course of the viral infection can be removed or retained, giving rise to distinct mRNAs with different coding capacities (Fields, 1996)+ Regulated intron retention also occurs in cellular genes+ One example is the Drosophila gene malespecific-lethal-2 (msl-2), which is involved in the control of X chromosome dosage compensation+ Dosage compensation in Drosophila occurs by hypertranscription in males of the single X chromosome (reviewed by Bashaw & Baker, 1996)+ This is achieved through the assembly on the X chromosome of a chromatin remodeling complex (MSL complex) that contains the protein MSL-2+ MSL-2 expression is inhibited in females, thus preventing MSL complex assembly and function+ Inhibition of msl-2 expression is related to retention of an intron present at the 59 untranslated sequence (UTR) of msl-2 transcripts in female flies (Bashaw & Baker, 1995;Kelley et al+, 1995;…”

Section: Introductionmentioning

confidence: 99%

Modulation of msl-2 5′ splice site recognition by Sex-lethal

Förch

Merendino

Martínez

et al. 2001

RNA

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The protein Sex-lethal (SXL) controls dosage compensation in Drosophila by inhibiting splicing and subsequently translation of male-specific-lethal-2 (msl-2) transcripts. We have previously shown that SXL blocks the binding of U2 auxiliary factor (U2AF) to the polypyrimidine (Py)-tract associated with the 39 splice site of the regulated intron. We now report that a second pyrimidine-rich sequence containing 11 consecutive uridines immediately downstream from the 59 splice site is required for efficient splicing inhibition by SXL. Psoralen-mediated crosslinking experiments suggest that SXL binding to this uridine-rich sequence inhibits recognition of the 59 splice site by U1 snRNP in HeLa nuclear extracts. We also show that SXL interferes with the binding of the protein TIA-1 to the uridine-rich stretch. Because TIA-1 binding to this sequence is necessary for U1 snRNP recruitment to msl-2 59 splice site and for splicing of this pre-mRNA, we propose that SXL antagonizes TIA-1 activity and thus prevents 59 splice site recognition by U1 snRNP. Taken together with previous data, we conclude that efficient retention of msl-2 intron involves inhibition of early recognition of both splice sites by SXL.

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Expression of Msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila

Cited by 292 publications

References 49 publications

Linking Global Histone Acetylation to the Transcription Enhancement of X-chromosomal Genes in Drosophila Males

Linking Global Histone Acetylation to the Transcription Enhancement of X-chromosomal Genes in Drosophila Males

roXRNAs Are Required for Increased Expression of X-Linked Genes inDrosophila melanogasterMales

Modulation of msl-2 5′ splice site recognition by Sex-lethal

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