The Dm-Myb Oncoprotein Contributes to Insulator Function and Stabilizes Repressive H3K27me3 PcG Domains

Santana, Juan Francisco de Paz; Parida, Mrutyunjaya; Long, Abby; Wankum, Joshua; Lilienthal, Anthony J.; Nukala, Krishna Madhav; Manak, J. Robert

doi:10.1016/j.celrep.2020.02.053

Cited by 8 publications

(7 citation statements)

References 71 publications

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“…DroID co-regulation analysis of downregulated genes showed an abundance of highly significant insulator proteins including CTCF, CP190, BEAF-32, Chro, mod(mdg4), and the dREAM repressive complex subunits Myb, E2F2, lin-52, mip120 and mip130 (fig. 6F, right) (Bohla et al, 2014; Santana et al, 2020). The reason for this might be connected to the strong downregulation of ribosomal RNA and tRNA-producing genes observed in our functional analyses.…”

Section: Resultsmentioning

confidence: 99%

Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence

Hutfilz

2022

Preprint

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Age is a fundamental aspect of biology that underlies the efficacy of a broad range of functions. Identifying determinants for how quickly or slowly we age will contribute greatly to our understanding of age as a modifier of overall health, particularly to the advancement of therapeutic interventions designed to mitigate or delay age-associated disorders. While much work has been devoted to the study of genetic or pharmacological interventions that extend lifespan, this approach does not necessarily recapitulate the physiological profile of naturally long-lived individuals. Diapause and diapause-like states constitute natural, inducible and evolutionarily conserved examples of lifespan plasticity that are well-suited to serve as physiologically accurate models of longevity. Here, we leveraged a metabolically critical signaling organ in Drosophila, the fat body, to examine diapause-associated transcription in the context of chromatin accessibility and the regulation of lifespan. Through a combination of ATAC-seq and RNA-seq, our observations suggest chromatin is globally reorganized in diapause and may assume a poised conformation to facilitate the rapid transcription of pro-development genes upon diapause termination. We found particular significance of GAF, NELF, and RNA polymerase III in this context. Congruently, transcription during diapause appears to favor many processes supporting the maintenance of cellular quiescence and the inhibition of differentiation. Our data are consistent with a model wherein diapause induces cellular quiescence in the fat body, as was additionally supported through fluorescent microscopy and comparison with public ChIP-seq data for developmentally juvenile files. This work opens the possibility that longevity in diapause may be partially determined through a lack of mitogenic signaling from the quiescent niche, concurrent with changes to the hormonal and immunological profiles that skew metabolism towards tissue maintenance.

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Section: Resultsmentioning

confidence: 99%

Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence

Hutfilz

2022

Preprint

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“…Indeed, we observed that CP190 still binds to most genomic sites associated with the Pita ΔCP1+2 protein in embryos. In many cases, these sites are associated with proteins that are known to be able to recruit CP190 [18,25,39,40,45,[65][66][67]. Such functional redundancy creates a stable and reliable architecture of regulatory elements, which is necessary for the correct regulation of genes during development.…”

Section: Discussionmentioning

confidence: 99%

Mechanism and functional role of the interaction between CP190 and the architectural protein Pita in Drosophila melanogaster

Sabirov

Kyrchanova

Pokholkova

et al. 2021

Epigenetics & Chromatin

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Background Pita is required for Drosophila development and binds specifically to a long motif in active promoters and insulators. Pita belongs to the Drosophila family of zinc-finger architectural proteins, which also includes Su(Hw) and the conserved among higher eukaryotes CTCF. The architectural proteins maintain the active state of regulatory elements and the long-distance interactions between them. In particular, Pita is involved in the formation of several boundaries between regulatory domains that controlled the expression of three hox genes in the Bithorax complex (BX-C). The CP190 protein is recruited to chromatin through interaction with the architectural proteins. Results Using in vitro pull-down analysis, we precisely mapped two unstructured regions of Pita that interact with the BTB domain of CP190. Then we constructed transgenic lines expressing the Pita protein of the wild-type and mutant variants lacking CP190-interacting regions. We have demonstrated that CP190-interacting region of the Pita can maintain nucleosome-free open chromatin and is critical for Pita-mediated enhancer blocking activity in BX-C. At the same time, interaction with CP190 is not required for the in vivo function of the mutant Pita protein, which binds to the same regions of the genome as the wild-type protein. Unexpectedly, we found that CP190 was still associated with the most of genome regions bound by the mutant Pita protein, which suggested that other architectural proteins were continuing to recruit CP190 to these regions. Conclusions The results directly demonstrate role of CP190 in insulation and support a model in which the regulatory elements are composed of combinations of binding sites that interact with several architectural proteins with similar functions.

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“…Indeed, we observed that CP190 still binds to most genomic sites associated with the Pita CP1+2 protein in embryos. In many cases, these sites are associated with proteins that are known to be able to recruit CP190 (25,(39)(40)(41)(62)(63)(64)(65). Such functional redundancy creates a stable and reliable architecture of regulatory elements, which is necessary for the correct regulation of genes during development.…”

Section: Discussionmentioning

confidence: 99%

Mechanism and functional role of the interaction between CP190 and the architectural protein Pita inDrosophila melanogaster

Sabirov

Kyrchanova

Pokholkova

et al. 2020

Preprint

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The architectural protein Pita is critical for Drosophila embryogenesis and predominantly binds to gene promoters and insulators. In particular, Pita is involved in the organization of boundaries between regulatory domains that controlled the expression of three hox genes in the Bithorax complex (BX-C). The best-characterized partner for Pita is the BTB/POZ-domain containing protein CP190. Using in vitro pull-down analysis, we precisely mapped two unstructured regions of Pita that interact with the BTB domain of CP190. Then we constructed transgenic lines expressing the Pita protein of the wild-type and mutant variants lacking CP190-interacting regions. The expression of the mutant protein completely complemented the null pita mutation. ChIP-seq experiments with wild-type and mutant embryos showed that the deletion of the CP190-interacting regions did not significantly affect the binding of the mutant Pita protein to most chromatin sites. However, the mutant Pita protein does not support the ability of multimerized Pita sites to prevent cross-talk between the iab-6 and iab-7 regulatory domains that activate the expression of Abdominal-B (Abd-B), one of the genes in the BX-C. The recruitment of a chimeric protein consisting of the DNA-binding domain of GAL4 and CP190-interacting region of the Pita to the GAL4 binding sites on the polytene chromosomes of larvae induces the formation of a new interband, which is a consequence of the formation of open chromatin in this region. These results suggested that the interaction with CP190 is required for the primary Pita activities, but other architectural proteins may also recruit CP190 in flies expressing only the mutant Pita protein.

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The Dm-Myb Oncoprotein Contributes to Insulator Function and Stabilizes Repressive H3K27me3 PcG Domains

Cited by 8 publications

References 71 publications

Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence

Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence

Mechanism and functional role of the interaction between CP190 and the architectural protein Pita in Drosophila melanogaster

Mechanism and functional role of the interaction between CP190 and the architectural protein Pita inDrosophila melanogaster

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