Cross-talk between signaling pathway and histone modifications in response to growth factor stimulation

Abstract

Despite being a growth factor, FGF-2 has anti-proliferative and tumor suppressive functions in some cellular contexts. In a murine adrenocortical tumor cell line (lineage Y1), FGF-2 triggers an initial mitogenic response through ERK1/2, PKC and AKT signaling but results in a G2/M cell cycle arrest through RhoA/GTP-src signaling. Recently, we found transcription factors related to early-gene responses (such as fosB and junB) that are differentially expressed after FGF-2 treatment. We also found a global decrease in chromatin active marks, such as acetylations of histone H4 N-terminus after 3 hours of FGF-2 stimulation. To better understand the dual phenotypic response (mitogenic versus cell cycle arrest) induced by FGF-2 we aim to perform a time-course quantitative proteomics analysis of histone PTMs and phosphoproteomics upon serum and FGF-2 stimulation in the Y1 cell line. An integration between signaling pathways and epigenetic changes induced by serum and/or FGF-2 will be performed in a systems biology perspective using bioinformatics tools. To our knowledge, high throughput analysis of cell signaling activation integrated to histone PTMs dynamics have been poorly explored in literature despite their importance in gene regulation. We believe that our work will shed light on how signaling pathways may interact with histone PTMs in both proliferative (serum stimulated cells) and non-proliferative (FGF-2 stimulated cells) responses. (AU)