CARM1 hypermethylates the NuRD chromatin remodeling complex to promote cell cycle gene expression and breast cancer development [ChIP-Seq]
The nucleosome remodeling and deacetylase (NuRD) complex is a large multi-subunit complex that couples ATP-dependent chromatin-remodeling and histone deacetylase activities. Emerging evidence suggested that NuRD are associated with active genes and modulates their expression, but the underlying molecular mechanisms remain ill-defined. Here, we reported that the transcriptional coactivator CARM1 is associated with NuRD through its direct interaction with the GATAD2A/2B subunit, expanding the activities of NuRD to include protein arginine methylation. CARM1 and NuRD co-bind and -activate a large cohort of genes with implications in cell cycle control to facilitate the G1 to S phase transition. This gene activation process requires CARM1 to hypermethylate a key subunit in the NuRD complex, GATAD2A/2B, which is critical for the recruitment of the NuRD complex. The biological significance of this gene activation mechanism is underscored by the high expression of CARM1 and NuRD in breast cancers, and the fact that knockdown CARM1 and NuRD inhibits breast cancer cell growth in vitro and tumorigenesis in vivo. These findings reveal a gene activation program that requires the dual specificity established by CARM1 on chromatin and a key chromatin remodeler. Overall design: ChIP-seq performed in this study was designed to understand the molecular mechanisms underlying CARM1/NuRD in gene transcriptional regulation.