Context-specific role of SOX9 in NF-Y mediated gene regulation in colorectal cancer cells.

Zhongcheng Shi,Yuko Mori-Akiyama,Toni-Ann Mistretta,Chi-I Chiang,Yanling Zhao,Jianhua Yang,Susan J Henning,Sankar N Maity,Paul Labhart

doi:10.1093/nar/gkv568

Abstract

Roles for SOX9 have been extensively studied in development and particular emphasis has been placed on SOX9 roles in cell lineage determination in a number of discrete tissues. Aberrant expression of SOX9 in many cancers, including colorectal cancer, suggests roles in these diseases as well and recent studies have suggested tissue- and context-specific roles of SOX9. Our genome wide approach by chromatin immunoprecipitation sequencing (ChIP-seq) in human colorectal cancer cells identified a number of physiological targets of SOX9, including ubiquitously expressed cell cycle regulatory genes, such as CCNB1 and CCNB2, CDK1, and TOP2A. These novel high affinity-SOX9 binding peaks precisely overlapped with binding sites for histone-fold NF-Y transcription factor. Furthermore, our data showed that SOX9 is recruited by NF-Y to these promoters of cell cycle regulatory genes and that SOX9 is critical for the full function of NF-Y in activation of the cell cycle genes. Mutagenesis analysis and in vitro binding assays provided additional evidence to show that SOX9 affinity is through NF-Y and that SOX9 DNA binding domain is not necessary for SOX9 affinity to those target genes. Collectively, our results reveal possibly a context-dependent, non-classical regulatory role for SOX9.

Highlights

SOX proteins, high-mobility group, (HMG)-box transcription factors, play crucial roles in embryonic and adult diverse tissues; these include maintenance of stem cell properties, lineage specification and terminal differentiation in a cell-type and tissue-specific manner
It is probably the case that the under-representation of SOX9 peaks in repeat masked regions cannot be explained by a difficulty of mapping reads to such regions, as the random peak control was generated based on a random sampling of mapped input reads; in addition, the majority of 50-nt reads are readily mapped to unique locations even in repeat masked regions (Supplementary Figure S1)
There has not been a report of genome-wide chromatin immunoprecipitation (ChIP) analysis in intestinal or there have been few reports identifying SOX9 targets in intestinal epithelium or colorectal cancer cells

Summary

Introduction

SOX proteins, high-mobility group, (HMG)-box transcription factors, play crucial roles in embryonic and adult diverse tissues; these include maintenance of stem cell properties, lineage specification and terminal differentiation in a cell-type and tissue-specific manner. SOX9 is expressed in the stem/progenitor cells, as well as in the nuclei of terminally differentiated Paneth cells of the small intestinal crypts and tuft cells in the villi and it plays a crucial role in Paneth cell differentiation [1,2]. There have been reports of opposing SOX9 functions, promoting and suppressing of proliferation, which suggest diverse, context-specific functions of SOX9 in proliferation. This has been shown in both developmental and cancer contexts. Differential roles of SOX9 have been demonstrated in normal intestinal epithelium; low SOX9 expression was associated with enhanced proliferative capacity and high SOX9 expression suppressed proliferation [6]. Another study showed that SOX9 expression facilitated growth and proliferation of colorectal cancer cells, whereas inactivation reduced tumorigenicity [7]

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Results

Conclusion