THE ALTERNATIVE SPLICING OF NF-YA REGULATES MOUSE EMBRYONIC STEM CELLS DIFFERENTIATION

Embryogenesis is governed by a fine balance between pluripotency and differentiation controlled by a handful of Transcription Factors (TFs). Some are implied in the maintenance of self-renewal and pluripotency of Embryonic Stem Cells (ESC), others drive cell lineage decisions which give rise to the entire organism. An example of these factors is NF-Y, a heterotrimeric pioneer TF promoting chromatin accessibility to other TFs to regulate gene expression. The regulatory subunit of NF-Y, NF-YA, recognizes and binds the CCAAT box motif, one of the most enriched DNA elements in enhancers and promoters of genes specifically active in ESCs. NF-YA exists in two different isoforms generated by Alternative Splicing of Exon 3. The short (NF-YAs) and the long (NF-YAl) isoforms differ from a stretch of 28-29 amino acids in the N-terminal Q-rich activation domain. Although they display identical DNA-binding properties in vitro, the two isoforms have distinct roles in several biological processes. Regarding embryogenesis, NF-YAs is the predominant isoform in undifferentiated mouse ESCs, being crucial for the regulation of pluripotency and stemness maintenance. By contrast, during Embryoid Bodies (EB) formation process, NF-YAl prevails, suggesting an implication of this specific isoform in the differentiation of mESCs. Our data strengthen the stem-related function of NF-YAs and propose a novel role of NF-YAl in mesoderm formation to shed light on the distinct functions of NF-YA isoforms in the equilibrium between pluripotency and differentiation.