The metastasis suppressor RRP1B interacts with TRIM28 and HP1 alpha at the c-MYC locus to induce heterochromatinization and silencing of c-MYC expression

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NHGRI	CANCER-7

* FARE Award Winner

Authors

• AM Dworkin
• M Lee
• J Lichtenberg
• SJ Patel
• D Gildea
• A Sakthianadeswaren
• S Foote
• TG Wolfsberg
• DM Bodine
• NPS Crawford

Abstract

Previous studies demonstrate that Rrp1b induces a gene expression signature that predicts survival in breast cancer. However, the mechanisms by which RRP1B modulates transcription are unclear. The aim of this study is to ascertain the mechanisms by which Rrp1b regulates metastasis-associated transcription. ChIP-seq analysis was performed to define genomic loci occupied by endogenous RRP1B. The consequences of this binding were investigated by quantifying the expression of genes containing or with nearby peaks in cells over-expressing RRP1B. We focused upon down regulated genes since RRP1B physically interacts with several heterochromatin-associated proteins. One gene with a nearby RRP1B occupancy peak was the oncogene and metastasis enhancer c-MYC. Ectopic expression of RRP1B reduced c-MYC expression levels. ChIP-reChIP using antibodies against RRP1B and TRIM28 or HP1α revealed that the c-MYC peak is bound by a complex containing all three proteins. ChIP using an antibody against H3K9me3 demonstrated that increased levels of H3K9me3 were evident at this locus. Our data indicate that RRP1B is directing the TRIM28/HP1α complex to the c-MYC locus to inhibit its transcription with concurrent increases in H3K9me3 levels. These observations provide insights into how RRP1B regulates transcription at the genome wide level, and a mechanism by which it suppresses metastasis.

back to top