Title: Genome-wide integrative analysis of transcription factor occupancy and gene regulation in models of human cancer and cellular differentiation
Description: Few transcription factors (TFs) have been studied in the context of an integrative analysis incorporating genomic datasets from diverse genome regulatory mechanisms. Such an analysis allows the testing of specific regulatory associations in an unbiased and comprehensive manner. The promoter binding TF complex NF-Y regulates a diverse set of constitutive, inducible, developmental, oncogenic and tissue-specific genes. Using cancer models, ChIP-Seq, shRNA, and genomics, I have undertaken a genome-wide study of NF-Y. NF-Y binds to not only promoters but also extensively to enhancers, select classes of repetitive elements, inactive chromatin domains and insulators. NF-Y is a "pioneer"-like factor able to access its motif within closed, transcriptionally inactive chromatin domains. NF-Y pervasively associates with FOS, usually in the absence of JUN and the AP-1 motif, and with a group of growth controlling oncogenic TFs. I also show that NF-Y asymmetrically binds to its motif and stereo-aligns with specific TFs and their motifs. My results indicate that NF-Y is not merely a commonly-used, proximal promoter TF, but rather functions at a more diverse set of genomic elements.