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Distinct structural transitions of chromatin topological domains coordinate hormone-induced gene regulation

ABSTRACT: The three-dimensional (3D) organization of the genome within the cell nucleus contributes to cell-specific gene expression in different cell types1. High-throughput 3C–derived methods have revealed that the genome is segmented into contiguous topologically associating domains (TADs), which help to orchestrate gene expression changes during differentiation and development2-5. Using ChIP-Seq, Hi-C and 3D modelling techniques, we reveal that TADs regulate the rapid gene expression changes induced by progestin in T47D breast cancer cells. In response to the hormone, TADs maintain their borders and operate as discrete regulatory units in which the majority of the genes are either transcriptionally activated or repressed. Additionally, the epigenetic signatures of the TADs are coordinately modified by hormone in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodelling are accompanied by structural changes that are distinct for activated or repressed TADs. Integrative 3D modelling revealed that TADs are structurally expanded if active and compacted if repressed, and that this is accompanied by differential changes in accessibility. We thus propose that TADs function as “regulons” to enable spatially proximal genes to be coordinately transcribed in response to hormones. T47D-MTVL human breast cancer cells were incubated with the progestin R5020 for different times at 37ºC and prepared for ChIP-Seq or Hi-C according published protocols

ORGANISM(S): Homo sapiens

SUBMITTER: Le Dily F

PROVIDER: S-ECPF-GEOD-53463 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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Project description:I-BAR proteins are well-known actin-cytoskeleton adaptors and have been observed to be involved in the formation of plasma membrane protrusions (filopodia). I-BAR proteins contain an all-helical, crescent-shaped IRSp53-MIM domain (IMD) dimer that is believed to be able to couple with a membrane shape. This coupling could involve the sensing and even the generation of negative plasma membrane curvature. Indeed, the in vitro studies have shown that IMDs can induce inward tubulation of liposomes. While N-BAR domains, which generate positive membrane curvature, have received a considerable amount of attention from both theory and experiments, the mechanisms of curvature coupling through IMDs are comparatively less studied and understood. Here we used a membrane-shape stability assay developed recently in our lab to quantitatively characterize IMD-induced membrane-shape transitions. We determined a membrane-shape stability diagram for IMDs that reveals how membrane tension and protein density can comodulate the generation of IMD-induced membrane protrusions. From comparison to analytical theory, we determine three key parameters that characterize the curvature coupling of IMD. We find that the curvature generation capacity of IMDs is significantly stronger compared to that of endophilin, an N-BAR protein known to be involved in plasma membrane shape transitions. Contrary to N-BAR domains, where amphipathic helix insertion is known to promote its membrane curvature generation, for IMDs we find that amphipathic helices inhibit membrane shape transitions, consistent with the inverse curvature that IMDs generate. Importantly, in both of these types of BAR domains, electrostatic interactions affect membrane-binding capacity, but do not appear to affect the curvature generation capacity of the protein. These two types of BAR domain proteins show qualitatively similar membrane shape stability diagrams, suggesting an underlying ubiquitous mechanism by which peripheral proteins regulate membrane curvature.

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Distinct structural transitions of chromatin topological domains coordinate hormone-induced gene regulation

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