Oct1 Is a Switchable, Bipotential Stabilizer of Repressed and Inducible Transcriptional States

Dean Tantin,Jinsuk Kang,Matthew A Williams,Arvind Shakya,Jeffrey Chumley

doi:10.1074/jbc.m110.174045

Abstract

Little is known regarding how the Oct1 transcription factor regulates target gene expression. Using murine fibroblasts and two target genes, Polr2a and Ahcy, we show that Oct1 recruits the Jmjd1a/KDM3A lysine demethylase to catalyze the removal of the inhibitory histone H3K9 dimethyl mark and block repression. Using purified murine T cells and the Il2 target locus, and a colon cancer cell line and the Cdx2 target locus, we show that Oct1 recruits the NuRD chromatin-remodeling complex to promote a repressed state, but in a regulated manner can switch to a different capacity and mediate Jmjd1a recruitment to block repression. These findings indicate that Oct1 maintains repression through a mechanism involving NuRD and maintains poised gene expression states through an antirepression mechanism involving Jmjd1a. We propose that, rather than acting as a primary trigger of gene activation or repression, Oct1 is a switchable stabilizer of repressed and inducible states.

Highlights

Loss of Oct1 inhibits oncogenic transformation in mouse embryonic fibroblasts (MEFs) and tumorigenicity in p53-deficient mice and xenograft assays, while having little effect on cell growth in culture or transformation by serial passage [9]
Oct1-facilitated Recruitment of Jmjd1a Mediates Polr2a and Ahcy Antirepression in Fibroblasts—We demonstrated previously that Oct1 possesses an antirepressive function at a target gene to which it binds following stress treatment (Polr2a): the locus is expressed in normal MEFs but is inappropriately repressed in Oct1-deficient MEFs
These results suggested that in fibroblasts lacking Oct1, negative regulatory marks inappropriately accumulate resulting in repression

Summary

Introduction

Loss of Oct1 inhibits oncogenic transformation in mouse embryonic fibroblasts (MEFs) and tumorigenicity in p53-deficient mice and xenograft assays, while having little effect on cell growth in culture or transformation by serial passage [9]. In resting but previously stimulated T cells, Oct1 is required to maintain Jmjd1a at Il2, remove histone H3K9me2 marks and protect DNA from methylation, promoting the stronger expression associated with secondary stimulation. No DNA methylation was observed following H2O2 treatment in either wild-type or Oct1-deficient MEFs for either Ahcy or Polr2a as assessed with bisulfite sequencing (supplemental Fig. S1).

Results

Conclusion