Differential Occupancy of Two GA-Binding Proteins Promotes Targeting of the Drosophila Dosage Compensation Complex to the Male X Chromosome

Kaye, Emily G.; Booker, Matthew J; Kurland, Jesse V.; Conicella, Alexander E.; Fawzi, Nicolas L.; Bulyk, Martha L.; Tolstorukov, Michael Y.; Larschan, Erica

doi:10.1016/j.celrep.2018.02.098

Cited by 42 publications

(93 citation statements)

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“…To evaluate this prediction and define factors that might contribute to this behavior, we computationally assessed a comprehensive repertoire of ChIP-seq data (Baumann and Gilmour, 2017;Henriques et al, 2018;Ho et al, 2014;Kaye et al, 2018;modENCODE Consortium et al, 2010;Weber et al, 2014). Specifically, we sought to identify factors enriched (or de-enriched) at gene promoters where pausing is unstable as compared to other promoters (see Methods).…”

Section: Resultsmentioning

confidence: 99%

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The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Elrod

Henriques

Huang

et al. 2019

Preprint

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Highlights:• The Integrator complex inhibits transcription elongation at ~15% of mRNA genes• Integrator targets promoter-proximally paused Pol II for termination• The RNA endonuclease of Integrator subunit 11 is critical for gene attenuation • Integrator-repressed genes are enriched in signaling and growth-responsive pathways SUMMARY The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25-60 nucleotide-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, a number of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA.Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.

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Section: Resultsmentioning

confidence: 99%

“…A comprehensive repertoire of ChIP-seq datasets from (Baumann and Gilmour, 2017;Henriques et al, 2018;Kaye et al, 2018;Lim et al, 2013;Weber et al, 2014) and…”

Section: Features Associated With Genes With Short-lived Promoter Polmentioning

confidence: 99%

The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Elrod

Henriques

Huang

et al. 2019

Preprint

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“…Since Larschan and colleagues suggested some competition in DNA-binding between CLAMP and GAF (Kaye et al, 2018), we explored whether the two proteins compete for binding to HAS in vivo. Upon RNAi depletion of GAF in male S2 cells the CLAMP ChIP-seq signal was unchanged at HAS (Figs.…”

Section: Msl2 Requires Clamp For Efficient Binding To Has In Vivomentioning

confidence: 99%

“…This assay locates the MSL2 interaction site to an Nterminal fragment of CLAMP, which harbors the first ZnF domain. The remaining 6 C-terminal ZnF domains are involved in binding to GA-dinucleotide repeats (Kaye et al, 2018;Kuzu et al, 2016;Soruco et al, 2013). Using various C-terminal deletion constructs of MSL2 showed that the ~200 C-terminal amino acids downstream of the CXC domain are required for interaction with CLAMP (Appendix S5A).…”

Section: Clamp and Msl2 Form A Stable Complexmentioning

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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“…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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Differential Occupancy of Two GA-Binding Proteins Promotes Targeting of the Drosophila Dosage Compensation Complex to the Male X Chromosome

Cited by 42 publications

References 50 publications

The Integrator complex terminates promoter-proximal transcription at protein-coding genes

The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Factor cooperation for chromosome discrimination in Drosophila

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

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