Thyroid Hormone Receptor Beta Suppression Of Runx2 Is Mediated By Brahma-Related Gene 1-Dependent Chromatin Remodeling

Thyroid hormone receptor beta (TR beta) suppresses tumor growth through regulation of gene expression, yet the associated TR beta-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TR beta-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TR beta. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TR beta. BRG1 and TR beta have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TR beta, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TR beta and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TR beta repression of oncogenic gene expression: TR beta recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TR beta transcriptional repression and tumor suppressor function in thyroid tumorigenesis.