What lies beneath the epigenetic signatures associated with breast cancer and how do we find out?

Epigenetic features such as DNA methylation status, histone modifications and chromatin states have been extensively profiled in the genome. Combinatorial epigenetic marks (epigenetic signatures) are emerging as breast cancer biomarkers and several studies are examining their diagnostic and prognostic value. However very little is still understood about the mechanisms that underlie aberrant epigenetic programming in cancer cells. A specific example is long range epigenetic silencing (LRES) where several contiguous genes are silenced simultaneously. We and others have shown that changes in chromatin conformation affects DNA methylation, histone modifications and the expression of genes within looping domains. New data from our studies in which genomic imprinting is used as a model system show that the expression of long noncoding RNA (lncRNA) can disrupt chromatin conformation and affect LRES through transcriptional interference. Since most of the genome actually consists of noncoding RNA, our results suggest that transcriptional interference and chromatin topology are interdependent. In addition to having cis functions as a result of their transcription, lncRNA can also have trans functions away from their site of transcription. Such trans functions are diverse but evidence is accumulating for lncRNAs having a role in recruiting chromatin remodelling proteins to specific regions of the genome. In a recent study in breast cancer cells we were able to uncouple the cis and trans functions of a lncRNA and showed that inhibition of a lncRNA increases genes involved in the c-Met signalling pathway leading to increased cell migration and cytoskeletal changes. This example of a lncRNA and its cis and trans functions is a vignette of epigenetic remodelling affecting the invasiveness and metastatic potential of breast cancer cells.