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Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.

ABSTRACT: Progesterone (P4)-activated progesterone receptors (PRs) play an essential role in driving pregnancy-associated mammary ductal side-branching morphogenesis and alveologenesis. However, the global cistromic and transcriptome responses that are required to elicit P4-dependent branching morphogenesis have not been elucidated. By combining chromatin immunoprecipitation followed by deep sequencing to identify genome-wide PR-binding sites in PR-positive luminal epithelial cells with global gene expression signatures acutely regulated by PRs in the mammary gland, we have identified a mammary epithelial PR targetome associated with active P4-dependent branching morphogenesis in vivo. We demonstrate that P4-induced side-branching is initiated by epithelial cell rearrangement into a multilayered epithelium that sprouts laterally from quiescent ducts via a mechanism requiring P4-dependent activation of Rac-GTPase signaling. We identify effectors of Rac-GTPases as direct transcriptional targets of PRs, and we demonstrate that disruption of the P4-activated Rac-GTPase signaling axis is sufficient to eliminate P4-dependent side-branching. Our data reveal that the molecular mediators of P4-dependent ductal side-branching overlap with those implicated in breast cancer.

SUBMITTER: Lain AR

PROVIDER: S-EPMC3787126 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.

Lain Ashlee R AR Creighton Chad J CJ Conneely Orla M OM

Molecular endocrinology (Baltimore, Md.) 20130826 10

Progesterone (P4)-activated progesterone receptors (PRs) play an essential role in driving pregnancy-associated mammary ductal side-branching morphogenesis and alveologenesis. However, the global cistromic and transcriptome responses that are required to elicit P4-dependent branching morphogenesis have not been elucidated. By combining chromatin immunoprecipitation followed by deep sequencing to identify genome-wide PR-binding sites in PR-positive luminal epithelial cells with global gene expres ...[more]

PMID: 23979845

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Project description:Pattern formation in developing tissues involves dynamic spatio-temporal changes in cellular organization and subsequent evolution of functional adult structures. Branching morphogenesis is a developmental mechanism by which patterns are generated in many developing organs, which is controlled by underlying molecular pathways. Understanding the relationship between molecular signaling, cellular behavior and resulting morphological change requires quantification and categorization of the cellular behavior. In this study, tissue-level and cellular changes in developing salivary gland in response to disruption of ROCK-mediated signaling by are modeled by building cell-graphs to compute mathematical features capturing structural properties at multiple scales. These features were used to generate multiscale cell-graph signatures of untreated and ROCK signaling disrupted salivary gland organ explants. From confocal images of mouse submandibular salivary gland organ explants in which epithelial and mesenchymal nuclei were marked, a multiscale feature set capturing global structural properties, local structural properties, spectral, and morphological properties of the tissues was derived. Six feature selection algorithms and multiway modeling of the data was performed to identify distinct subsets of cell graph features that can uniquely classify and differentiate between different cell populations. Multiscale cell-graph analysis was most effective in classification of the tissue state. Cellular and tissue organization, as defined by a multiscale subset of cell-graph features, are both quantitatively distinct in epithelial and mesenchymal cell types both in the presence and absence of ROCK inhibitors. Whereas tensor analysis demonstrate that epithelial tissue was affected the most by inhibition of ROCK signaling, significant multiscale changes in mesenchymal tissue organization were identified with this analysis that were not identified in previous biological studies. We here show how to define and calculate a multiscale feature set as an effective computational approach to identify and quantify changes at multiple biological scales and to distinguish between different states in developing tissues.

Dataset Information

Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.

Publications

Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.

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