Transcriptomics,Multiomics

Dataset Information

51

Coordinated epigenetic remodelling occurs during early breast carcinogenesis [Human promoter ChIP-chip]


ABSTRACT: 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 normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. H3K27me3 ChIP-chip was performed on HMEC and vHMEC from 4 donors, H3K9ac was performed on cells from 2 donors. Both H3K27me3 and H3K9ac ChIP was performed on two time points for vHMEC and used the same input materia.

ORGANISM(S): Homo sapiens  

SUBMITTER: Warwick J Locke  Warwick James Locke    

PROVIDER: E-GEOD-58880 | ArrayExpress | 2015-05-22

SECONDARY ACCESSION(S): GSE58880PRJNA253806

REPOSITORIES: GEO, ArrayExpress

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Publications

Coordinated epigenetic remodelling of transcriptional networks occurs during early breast carcinogenesis.

Locke Warwick J WJ   Zotenko Elena E   Stirzaker Clare C   Robinson Mark D MD   Hinshelwood Rebecca A RA   Stone Andrew A   Reddel Roger R RR   Huschtscha Lily I LI   Clark Susan J SJ  

Clinical epigenetics 20150501


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  ...[more]

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