Epigenetic Spreading of the Drosophila Dosage Compensation Complex from roX RNA Genes into Flanking Chromatin

Kelley, R. L.; Meller, Victoria H.; Gordadze, Polina R.; Roman, Gregg; Davis, Ronald L.; Kuroda, Mitzi I.

doi:10.1016/s0092-8674(00)81979-0

Cited by 288 publications

(386 citation statements)

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“…Histology: Immunhistochemical detection of MSL3, MOF, and H4Ac16 on polytene chromosomes was done as previously described (Kelley et al 1999). Rabbit anti-H4Ac16 was purchased from Serotec (Raleigh, NC).…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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

Deng

Meller

2006

Genetics

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“…However, the discovery that MSL1 and MSL2 could bind to a reproducible subset of 35-70 sites (including the roX genes) in the absence of the other MSL proteins led to the proposal of the "entry and spreading" model (for review, see Kelley and Kuroda 2000). Accordingly, the MSL proteins were proposed to recognize the X via the ∼35 high-affinity "entry sites," from where they could spread to bind the remaining target sites by an unknown mechanism (Lyman et al 1997;Kelley et al 1999). Recent studies of flies with altered DCC concentrations, X to autosome translocations, and analysis of new "entry sites" suggest that the entry sites are simply high-affinity sites in a continuum of affinity sites dispersed along the X chromosome (Demakova et al 2003;Fagegaltier and Baker 2004;Oh et al 2004b;Dahlsveen et al 2006).…”

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confidence: 99%

Chromosome-wide gene-specific targeting of theDrosophiladosage compensation complex

Gilfillan¹,

Straub²,

Wit³

et al. 2006

Genes Dev.

147

209

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The dosage compensation complex (DCC) of Drosophila melanogaster is capable of distinguishing the single male X from the other chromosomes in the nucleus. It selectively interacts in a discontinuous pattern with much of the X chromosome. How the DCC identifies and binds the X, including binding to the many genes that require dosage compensation, is currently unknown. To identify bound genes and attempt to isolate the targeting cues, we visualized male-specific lethal 1 (MSL1) protein binding along the X chromosome by combining chromatin immunoprecipitation with high-resolution microarrays. More than 700 binding regions for the DCC were observed, encompassing more than half the genes found on the X chromosome. In addition, several rare autosomal binding sites were identified. Essential genes are preferred targets, and genes binding high levels of DCC appear to experience the most compensation (i.e., greatest increase in expression). DCC binding clearly favors genes over intergenic regions, and binds most strongly to the 3 end of transcription units. Within the targeted genes, the DCC exhibits a strong preference for exons and coding sequences. Our results demonstrate gene-specific binding of the DCC, and identify several sequence elements that may partly direct its targeting.[Keywords: Transcription; histone modification; chromatin remodeling; MSL complex; microarray; gene expression] Supplemental material is available at http://www.genesdev.org.

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“…(16)(17)(18) A compelling argument has been made for the role of LINE-1 elements, enriched on the mammalian X chromosome, in supporting the spread of silencing. (19,20) The Drosophila X chromosome is enriched in particular satellite sequences and repeats, (21)(22)(23) as is the C. elegans X chromosome.…”

Section: How Important Is Spreading?mentioning

confidence: 99%

“…One intriguing idea is that cis-acting fly elements promote the adoption of compensation by genes newly relocated to the X chromosome, thus playing an evolutionary role. (18) In C. elegans, as in mammals, recognition elements now appear likely to form the basis of X recognition. Targeting of the DCC depends on the SDC2 protein, which together with SDC3 recruits the DCC to X chromosomes.…”

Section: The Uses Of Recognition Elementsmentioning

confidence: 99%

Worm chromosomes call for recognition!

Rattner¹,

Meller²

2004

BioEssays

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SummaryMany organisms face a dilemma rooted in the unequal numbers of X chromosomes carried by the two sexes and the need to maintain equivalent expression of X-linked genes. Several strategies have arisen to cope with this problem. All rely on accurately targeting epigenetic modifications to entire chromosomes. Targeting results from the action of recognition elements that attract modification and may rely on spreading of modification in cis along the affected chromosome. A recent report describing the first X chromosome recognition element from C. elegans opens the way to defining the relative contributions of these factors to the compensation of Xlinked gene expression in worms. (1) Extrachromosomal arrays composed of a C. elegans recognition element attract proteins that modify the C. elegans X chromosomes and interact genetically with mutations disrupting compensation. Moreover, examination of X:A translocations provides the first evidence for spreading of modification along C. elegans X chromosomes. Dosage compensation: one problem with different solutions One of the primary distinctions between the sexes of many species is the number of sex chromosomes. The heterogametic sex (XY or X0) typically results in male development, and female or hermaphrodite development occurs in the sex carrying two copies of the same chromosome (XX). As most X-linked genes encode functions that are required equally in both sexes, inequality in the number of sex chromosomes poses a fundamental challenge: the need for a mechanism that ensures the production of similar amounts of X-linked gene products regardless of the number of X chromosomes present. At least three different solutions have independently evolved in mammals, flies and the worm C. elegans. These strategies, grouped under the term 'dosage compensation', appear different at a first glance but present remarkable similarities. In mammals, dosage compensation between XY males and XX females occurs by the transcriptional silencing of one randomly chosen X chromosome in each female cell. (2) In flies, XY males increase transcription from most X-linked genes. (3) Hermaphrodite worms (XX) continue to transcribe both X chromosomes, but at half the rate of the single male X. (4) These divergent strategies arrive at a similar outcome: both sexes express similar amounts of most X-linked gene products. Each mechanism is based on the recruitment of chromatin-modifying factors to the X chromosome. These factors achieve a stable, epigenetic modification of chromatin structure resulting in altered gene expression, the central feature of dosage compensation.Targeting the X chromosome A shared requirement of each system is the need to accurately target modification to an entire chromosome, or in C. elegans, a pair of X chromosomes. An element of danger is implicit in the mammalian strategy as silencing is directed to one chromosome, but the identical homologue must remain active. This dilemma is solved by designating a single X inactivation center (Xic) to direct X inactivation in ci...

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Epigenetic Spreading of the Drosophila Dosage Compensation Complex from roX RNA Genes into Flanking Chromatin

Cited by 288 publications

References 50 publications

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

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

Chromosome-wide gene-specific targeting of theDrosophiladosage compensation complex

Worm chromosomes call for recognition!

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