Abstract A46: Regulation of genomic Myc binding by Pin1 in serum-stimulated fibroblasts

Abstract

Abstract The transcription factor Myc's induction of its pro-oncogenic target genes is regulated by Serine62 (S62) phosphorylation and the Pin1 prolyl-isomerase, where pS62-Myc is isomerized at Proline63 by Pin1 and this facilitates its recruitment to select target gene promoters. It is also known that Myc is an early serum response gene that controls cellular transition from quiescence to proliferation. In order to examine the global effects of Pin1 on Myc activity, we have performed unbiased genome-wide RNA-seq and ChIP-seq for Myc in primary murine embryo fibroblasts (MEFs) derived from Pin1 wild-type and knockout mice. The MEFs were serum starved for 72 hours and serum stimulated for 4 hours. Through RNA-seq we have observed a striking blunting of serum responsive genes in the Pin1 null cells. From our highly reproducible ChIP-seq data (6719 regions, IDR<0.1, Pin1 wild-type, stimulated), we found that both the number and magnitude of Myc DNA binding peaks were reduced in the null cells in genes showing blunted serum response. Using functional annotation analysis tools (DAVID and GSEA), we found opposing pathway-enrichments for Myc binding in null versus wild-type cells, with proliferation and migration genes enriched in wild-type cells. Furthermore, binding motif analysis of Myc-binding sites suggested a stronger enrichment of canonical E-box motif (CACGTG) in wild-type cells over null cells. In summary, our study suggested a key role that Pin1 plays in Myc global DNA binding activity. Citation Format: Yulong Su, Carl Pelz, Soren Impey, Rosalie Sears. Regulation of genomic Myc binding by Pin1 in serum-stimulated fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A46.