title: Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation.
abstract: Breast and ovarian cancer susceptibility genes BRCA1 and PALB2 have enigmatic roles in cellular growth and mammalian development. While these genes are essential for growth during early developmental programs, inactivation later in adulthood results in increased growth and formation of tumors, leading to their designation as tumor suppressors. We performed genome-wide analysis assessing their chromatin residence and gene expression responsiveness using high-throughput sequencing in breast epithelial cells. We found an intimate association between BRCA1 and PALB2 chromatin residence and genes displaying high transcriptional activity. Moreover, our experiments revealed a critical role for BRCA1 and, to a smaller degree, PALB2 in transcriptional responsiveness to NF-κB, a crucial mediator of growth and inflammatory response during development and cancer. Importantly, we also uncovered a vital role for BRCA1 and PALB2 in response to retinoic acid (RA), a growth inhibitory signal in breast cancer cells, which may constitute the basis for their tumor suppressor activity. Taken together, our results highlight an important role for these breast cancer proteins in the regulation of diverse growth regulatory pathways.
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gardini
authors.forename: David
authors.initials: D
authors.lastname: Baillat
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.forename: Ramin
authors.initials: R
authors.lastname: Shiekhattar
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D000076164:Fanconi Anemia Complementation Group N Protein; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002843:Chromatin; D000076164:Fanconi Anemia Complementation Group N Protein; D016328:NF-kappa B; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D014212:Tretinoin