Chromatin profiles of human cells in health and disease using FAIRE

PAUL G. GIRESI: Chromatin profiles of human cells in health and disease using FAIRE (Under the direction of Jason D. Lieb) Breast cancer is a heterogenous disease comprised of molecularly distinct subtypes with diverse clinical outcomes. Understanding the molecular composition of each subtype will aid in the effective diagnosis and treatment of breast cancer. The composition and activity of subtype-selective regulatory pathways operate, in part, through binding of proteins at distinct sites throughout the genome, often referred to as regulatory elements, to govern levels of gene expression. One of the characteristics of these binding events is the displacement of nucleosomes. Here we have developed a technique called FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements), which is capable of the genome-wide identification of active regulatory elements in human cells based on the nucleosome-depleted nature of these sites. Using FAIRE we have identified the genome-wide set of active regulatory elements in the luminal and basal-like tumor subtypes. Here most of the active regulatory elements were distinct to each subtype. Many of these unique sites also reflected the activity of the regulatory mechanisms present in a given subtype. For example, in the hormone-responsive luminal cells we detected strong FAIRE signals at estrogen-receptor alpha binding sites, whereas the signals are diminished or absent in the hormone nonresponsive basal-like cells. These subtype-selective regulatory elements tended to be clustered around the set of expressed genes in the respective subtype, regardless of whether the gene was differentially expressed between the subtypes. The subtypeselective regulatory elements were also enriched with sequence motifs for DNA-binding