Dataset Information

Epigenetic and transcriptional determinants of the human breast.

ABSTRACT: While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.

SUBMITTER: Gascard P

PROVIDER: S-EPMC4346612 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetic and transcriptional determinants of the human breast.

Gascard Philippe P Bilenky Misha M Sigaroudinia Mahvash M Zhao Jianxin J Li Luolan L Carles Annaick A Delaney Allen A Tam Angela A Kamoh Baljit B Cho Stephanie S Griffith Malachi M Chu Andy A Robertson Gordon G Cheung Dorothy D Li Irene I Heravi-Moussavi Alireza A Moksa Michelle M Mingay Matthew M Hussainkhel Angela A Davis Brad B Nagarajan Raman P RP Hong Chibo C Echipare Lorigail L O'Geen Henriette H Hangauer Matthew J MJ Cheng Jeffrey B JB Neel Dana D Hu Donglei D McManus Michael T MT Moore Richard R Mungall Andrew A Ma Yussanne Y Plettner Patrick P Ziv Elad E Wang Ting T Farnham Peggy J PJ Jones Steven J M SJ Marra Marco A MA Tlsty Thea D TD Costello Joseph F JF Hirst Martin M

Nature communications 20150218

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we def ...[more]

PMID: 25690954

Similar Datasets

Project description:Dysregulation of the epigenome is a common event in malignancy; however, deciphering the earliest cancer-associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of human mammary epithelial cells (HMEC) and a matched variant cell population (vHMEC) that have spontaneously escaped senescence and undergone partial carcinogenic transformation. Using this model of basal-like breast carcinogenesis, we provide striking new insights into the very first epigenetic changes that occur during the initial stages of malignancy.The first phase of malignancy is defined by coordinated changes in the epigenome. At the chromatin level, this is embodied in long-range epigenetic deregulation, which involves the concomitant but atypical acquisition or loss of active and repressive histone modifications across large regional blocks. Changes in DNA methylation also occurs in a highly coordinated manner. We identified differentially methylated regions (DMRs) in the very earliest passages of vHMECs. Notably, we find that differential methylation targets loci regulated by key transcription factors including p53, AHR and E2F family members suggesting that epigenetic deregulation of transcription factor binding is a key event in breast carcinogenesis. Interestingly, DMRs identified in vHMEC are extensively methylated in breast cancer, with hypermethylation frequently encroaching into neighbouring regions. A subset of vHMEC DMRs exhibited a strong basal-like cancer specific hypermethylation.Here, we generated epigenome-wide maps of the earliest phase of breast malignancy and show long-range epigenetic deregulation and coordinated DNA hypermethylation targets loci regulated by key transcription factors. These findings support a model where induction of breast cancer occurs through epigenetic disruption of transcription factor binding leading to deregulation of cancer-associated transcriptional networks. With their stability and very early occurrence, vHMECs hypermethylated loci could serve as excellent biomarkers for the initial detection of basal breast cancer.

Dataset Information

Epigenetic and transcriptional determinants of the human breast.

Publications

Epigenetic and transcriptional determinants of the human breast.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets