Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation

Kuzu, Guray; Kaye, Emily G.; Chery, Jessica; Siggers, Trevor; Yang, Lin; Dobson, Jason R.; Boor, Sonia; Bliss, Jacob E.; Liu, Wei; Jogl, G.; Rohs, Remo; Singh, Nadia D.; Bulyk, Martha L.; Tolstorukov, Michael Y.; Larschan, Erica

doi:10.1371/journal.pgen.1006120

Cited by 53 publications

(109 citation statements)

References 61 publications

(109 reference statements)

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“…They termed this protein CLAMP (Chromatin Linked Adaptor for MSL Proteins) since depletion of the protein leads to dissociation of the DCC from the X chromosome Soruco et al, 2013). CLAMP is an essential protein in Drosophila independent of sex, which binds thousands of GA-rich sequences genome-wide (Kuzu et al, 2016;Soruco et al, 2013;Urban et al, 2017b) and therefore does not qualify as a determinant of X-specificity. Remarkably, CLAMP binds to HAS only in male cells, suggesting a functional relationship with the DCC (Soruco et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Factor cooperation for chromosome discrimination in Drosophila

Albig

Tikhonova

Krause

et al. 2018

Preprint

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Transcription regulators select their genomic binding sites from a large pool of similar, non-functional sequences. Although general principles that allow such discrimination are known, the complexity of DNA elements often precludes a prediction of functional sites.The process of dosage compensation in Drosophila allows exploring the rules underlying binding site selectivity. The male-specific-lethal (MSL) Dosage Compensation Complex selectively binds to some 300 X-chromosomal 'High Affinity Sites' (HAS) containing GA-rich 'MSL recognition elements' (MREs), but disregards thousands of other MRE sequences in the genome. The DNA-binding subunit MSL2 alone identifies a subset of MREs, but fails to recognize most MREs within HAS. The 'Chromatin-linked adaptor for MSL proteins' (CLAMP) also interacts with many MREs genome-wide and promotes DCC binding to HAS. Using genome-wide DNA-immunoprecipitation we describe extensive cooperativity between both factors, depending on the nature of the binding sites. These are explained by physical interaction between MSL2 and CLAMP. In vivo, both factors cooperate to compete with nucleosome formation at HAS. The male-specific MSL2 thus synergises with a ubiquitous GA-repeat binding protein for refined X/autosome discrimination. KeywordsATAC-seq/ CLAMP/ DNA-immunoprecipitation/ Dosage compensation/ MSL2

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Section: Introductionmentioning

confidence: 99%

Factor cooperation for chromosome discrimination in Drosophila

Albig

Tikhonova

Krause

et al. 2018

Preprint

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“…We validated our algorithm against the Drosophila genome, confirming previously published findings that the densities of GA-repeats are enriched ≥2fold on the X chromosome relative to autosomes ( Supplemental Table I). For example, GA-repeat lengths from 8 bp to 28 bp, experimentally validated in MSL and CLAMP binding assays in vitro and in vivo 18,23,27 , occur on the X chromosome at densities ≥1.0/Mb, with an average X:A density enrichment of 2.5-fold ( Figure 1a).…”

Section: Resultsmentioning

confidence: 97%

“…CLAMP acts locally at CES/HAS sites and at a distance with GAF to recruit the MSL complex and to shape the overall architecture of the X chromosome [22][23][24] .…”

Section: Resultsmentioning

confidence: 99%

GA-repeats on mammalian X chromosomes support Ohno’s hypothesis of dosage compensation by transcriptional upregulation

D’Souza

Weinand³

et al. 2018

Preprint

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Over 50 years ago, Susumo Ohno proposed that dosage compensation in mammals would require upregulation of gene expression on the single active X chromosome, a mechanism which to date is best understood in the fruit fly Drosophila melanogaster. Here, we report that the GA-repeat sequences that recruit the conserved MSL dosage compensation complex to the Drosophila X chromosome are also enriched across mammalian X chromosomes, providing genomic support for the Ohno hypothesis. We show that mammalian GA-repeats derive in part from transposable elements, suggesting a mechanism whereby unrelated X chromosomes from dipterans to mammals accumulate binding sites for the MSL dosage compensation complex through convergent evolution, driven by their propensity to accumulate transposable elements.

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“…Rieder, Jordan and Larschan Alekseyenko et al 2008) . However, MREs are only twofold enriched on the Xchromosome compared to autosomes (Kuzu et al, 2016) . Furthermore, targeting of MSLc also requires the sixzinc finger transcription factor, Chromatin Linked Adaptor for MSL Proteins (CLAMP) (Soruco et al, 2013) , although CLAMP targets MREs genomewide and is not unique to the Xchromosome (Kaye et al, 2017; Rieder et al, 2017; Urban et al, 2017 .…”

Section: Introductionmentioning

confidence: 92%

Targeting of the dosage-compensated male X-chromosome during earlyDrosophiladevelopment

Rieder

Jordan

Larschan

2019

Preprint

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The essential process of dosage compensation, which corrects for the imbalance in Xlinked gene expression between XX females and XY males, represents a key model for how genes are targeted for coordinated regulation. However, the mechanism by which dosage compensation complexes identify the Xchromosome during early development remained unknown because of the difficulty of sexing embryos prior to zygotic transcription. We used meiotic drive to sex Drosophila embryos prior to zygotic transcription and ChIPseq to measure dynamics of dosage compensation factor targeting. The Drosophila MaleSpecific Lethal dosage compensation complex (MSLc) requires the ubiquitous zincfinger protein ChromatinLinked Adaptor for MSL Proteins (CLAMP) to identify the Xchromosome. We observe a multistage process in which MSLc first identifies CLAMP binding sites throughout the genome followed by concentration at the strongest Xlinked MSLc sites. We provide insight into the dynamic mechanism by which a large transcription complex identifies its binding sites during early development.

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Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation

Cited by 53 publications

References 61 publications

Factor cooperation for chromosome discrimination in Drosophila

Factor cooperation for chromosome discrimination in Drosophila

GA-repeats on mammalian X chromosomes support Ohno’s hypothesis of dosage compensation by transcriptional upregulation

Targeting of the dosage-compensated male X-chromosome during earlyDrosophiladevelopment

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