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Crosstalk between chromatin and the transcription factor Svb

ABSTRACT: The transcription factor Shavenbaby (Svb), the only member of the OvoL family in Drosophila, controls intestinal stem cell differentiation. Post-translational modification of Svb produces two protein isoforms, Svb-ACT and Svb-REP, which promote intestinal stem cell renewal or differentiation, respectively. Using engineered cell lines, we express either isoform to define their mode of action, and develop an unbiased method to identify Svb target genes in intestinal cells. Within a given cell type, Svb-ACT and Svb-REP antagonistically regulate the expression of a set of target genes, binding specific enhancers whose accessibility is constrained by. During intestinal differentiation, the set of target genes progressively changes, together with chromatin accessibility. Moreover, Svb-REP binding stabilizes three-dimensional enhancer-promoter loops, while influencing the local chromatin landscape to repress target genes. We propose that SvbACT-to-REP switch promotes enterocyte differentiation of intestinal stem cells through direct gene regulation and chromatin remodeling.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE221863 | GEO | 2024/01/12

REPOSITORIES: GEO

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Project description:Developmental programs are implemented by regulatory interactions between Transcription Factors (TFs) and their target genes, which remain yet poorly understood. While recent studies have focused on regulatory cascades of TFs that govern early development, little is known on how these are selected and controlled the ultimate cellular effectors of terminal differentiation. We addressed this question during late Drosophila embryogenesis when the finely tuned expression of a TF, Ovo/Shavenbaby (Svb), triggers the morphological differentiation of epidermal trichomes. We used chromatin immunoprecipitation and microarray profiling to identify Svb downstream target genes and show that Svb directly regulates a large set of terminal effectors of trichome formation. Functional assays delineated 18 Svb bound sequences driving specific expression of trichome effectors, with highly similar pattern and dynamics. Coupling computational modeling to functional dissection, we further investigated the regulatory logic of these enhancers. We find that these “terminal” enhancers harbor remarkable features with respect to their functional architectures. Trichome enhancers display weak if any clustering of Svb binding sites. Moreover, the in vivo function of each site relies on its intimate context, with a critical importance of the nucleotides flanking Svb binding sites. Finally, we identify additional cis-regulatory motifs, showing a broad diversity of positioning among trichome enhancers, and that critically contribute to their activity. Taken together, these results show that trichome formation is underpinned by unexpectedly diverse modes of regulation, and shed light on the functional architecture of enhancers governing a terminal differentiation program. Chromatin from 12-14 hour old embryos expressing svb tagged with GFP (Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P, Hashimoto Y, Kobayashi S, Payre F, Kageyama Y: Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 2010, 329:336-339) was collected in duplicate. Chromatin was immunoprecipitated using an antiGFP antibody and input chromatin was used as a control.

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Crosstalk between chromatin and the transcription factor Svb

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