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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE116386 | GEO | 2018/06/29

REPOSITORIES: GEO

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Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity.

Project description:Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [RNA-seq]

Project description:We performed RNA-seq on normal mammary cell populations and mouse mammary tumor cell populations

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ChIP-seq]

Project description:We performed H3K27ac ChIP-seq on normal mammary cell populations and SOX10 ChIP-seq on PY230 tumors

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ATAC-seq]

Project description:We performed ATAC-seq on normal mammary cell populations and mouse mammary tumor cell populations

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity

Project description:Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ChIP-seq]

Project description:Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ChIP-seq]

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [RNA-seq]

Project description:Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [RNA-seq]

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Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ATAC-seq]

Project description:Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [ATAC-seq]

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Single-Cell Chromatin Analysis of Mammary Gland Development Reveals Cell-State Transcriptional Regulators and Lineage Relationships.

Project description:Technological improvements enable single-cell epigenetic analyses of organ development. We reasoned that high-resolution single-cell chromatin accessibility mapping would provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal mammary gland development. Here, we provide a single-cell resource of chromatin accessibility for murine mammary development from the peak of fetal mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity. The ability of single-cell chromatin profiling to separate E18 fetal mammary cells into clusters exhibiting basal-like and luminal-like chromatin features is noteworthy. Such distinctions were not evident in analyses of droplet-based single-cell transcriptomic data. We present a web application as a scientific resource for facilitating future analyses of the gene regulatory networks involved in mammary development.

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Project description:Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conformation initiated by DNA methylation, histone variants, post-translational modifications of histones, non-histone chromatin proteins, and non-coding RNAs. Epigenetics plays a key role in development. However, very little is known about its role in the developing mammary gland or how it might integrate the many signalling pathways involved in mammary gland development and function that have been discovered during the past few decades. An inverse relationship between marks of closed (DNA methylation) or open chromatin (DnaseI hypersensitivity, certain histone modifications) and milk protein gene expression has been documented. Recent studies have shown that during development and functional differentiation, both global and local chromatin changes occur. Locally, chromatin at distal regulatory elements and promoters of milk protein genes gains a more open conformation. Furthermore, changes occur both in looping between regulatory elements and attachment to nuclear matrix. These changes are induced by developmental signals and environmental conditions. Additionally, distinct epigenetic patterns have been identified in mammary gland stem and progenitor cell sub-populations. Together, these findings suggest that epigenetics plays a role in mammary development and function. With the new tools for epigenomics developed in recent years, we now can begin to establish a framework for the role of epigenetics in mammary gland development and disease.

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