RT Journal
A1 Franco, Hector L.
A1 Nagari, Anusha
A1 Malladi, Venkat S.
A1 Li, Wenqian
A1 Xi, Yuanxin
A1 Richardson, Dana
A1 Allton, Kendra L.
A1 Tanaka, Kaori
A1 Li, Jing
A1 Murakami, Shino
A1 Keyomarsi, Khandan
A1 Bedford, Mark T.
A1 Shi, Xiaobing
A1 Li, Wei
A1 Barton, Michelle C.
A1 Dent, Sharon Y.R.
A1 Kraus, W. Lee
T1 Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis
JF Genome Research 
JO Genome Research 
YR 2018 
FD February 01 
VO 28 
IS 2 
SP 159 
OP 170 
DO 10.1101/gr.226019.117 
UL http://genome.cshlp.org/content/28/2/159.abstract 
AB Noncoding transcription is a defining feature of active enhancers, linking transcription factor (TF) binding to the molecular mechanisms controlling gene expression. To determine the relationship between enhancer activity and biological outcomes in breast cancers, we profiled the transcriptomes (using GRO-seq and RNA-seq) and epigenomes (using ChIP-seq) of 11 different human breast cancer cell lines representing five major molecular subtypes of breast cancer, as well as two immortalized (“normal”) human breast cell lines. In addition, we developed a robust and unbiased computational pipeline that simultaneously identifies putative subtype-specific enhancers and their cognate TFs by integrating the magnitude of enhancer transcription, TF mRNA expression levels, TF motif P-values, and enrichment of H3K4me1 and H3K27ac. When applied across the 13 different cell lines noted above, the Total Functional Score of Enhancer Elements (TFSEE) identified key breast cancer subtype-specific TFs that act at transcribed enhancers to dictate gene expression patterns determining growth outcomes, including Forkhead TFs, FOSL1, and PLAG1. FOSL1, a Fos family TF, (1) is highly enriched at the enhancers of triple negative breast cancer (TNBC) cells, (2) acts as a key regulator of the proliferation and viability of TNBC cells, but not Luminal A cells, and (3) is associated with a poor prognosis in TNBC breast cancer patients. Taken together, our results validate our enhancer identification pipeline and reveal that enhancers transcribed in breast cancer cells direct critical gene regulatory networks that promote pathogenesis.