ON THE NF-Y REGULOME IN DIFFERENT CELLS

NF-Y is a trimeric sequence-specific transcription factor (TF) that binds the conserved CCAAT-box DNA element. Upon their dimerization, the histone-like subunits NF-YB and NF-YC interact with the DNA-binding subunit, NF-YA. The CCAAT-box is enriched in promoters of genes deregulated in cancer. As a pioneer TF, NF-Y plays a relevant role in organizing chromatin nearby transcription start sites as well as recruiting other factors and cofactors. The growing ENCODE repository stores ChIP-seq data of hundreds of transcription factors and cofactors in various cell lines. The integration of TFs ChIP-seq datasets is a useful resource for building genome-wide regulatory networks around DNA binding proteins. By integrating the available data about TFs in the ENCODE compendium, we outlined groups of NF-Y TFs modules involved in the regulation of gene expression in human genome, according to different criteria and implementing a computational pipeline developed by us. NF-Y is involved in the control of different basic cellular activities, such as cell cycle progression and cellular metabolism in normal and transformed cells. NF-YA exists in two different isoforms, NF-YAs (short) and NF-YAl (long), differing in 28 amino acids, coded by exon 3 and being part of the trans-activation domain. The short NF-YA is involved in stemness maintenance of mouse embryonic stem cells. In mouse muscle satellite cells, we found that NF-YA expression is fundamental to preserve the pool of muscle stem cells and its loss triggers DNA damage. On the other side, in epithelial tumors, there is evidence that NF-Y may play a role due to its regulatory function in cell cycle. Inspecting TCGA bulk RNA-seq data and deconvoluting it from scRNA-seq in various epithelial cancer datasets, we discovered that NF-YA is up-regulated in all investigated tumors, whereas histone-like subunits are more variable. Specifically, NF-YAs is primarily overexpressed in CCAAT-driven cell cycle related molecular subtypes, whereas NF-YAl isoform tends to correlate with mesenchymal and metastasis-prone identity.