Promyelocytic Leukemia Protein in Retinoic Acid‐Induced Chromatin Remodeling of Oct4 Gene Promoter

Promyelocytic leukemia (Pml) protein is required for Oct4 gene expression and the maintenance of its open chromatin conformation in stem cells. In proliferating stem cells, Pml‐nuclear body, along with transcription factors TR2, steroidogenic factor 1 (SF1) and Sp1, and Brg1‐dependent chromatin remodeling complex (BRGC), associates with conserved region 1 (CR1) of this promoter to maintain a nucleosome‐free region for gene activity. Retinoic acid (RA) rapidly downregulates Pml, resulting in the replacement of BRGC with Brm‐containing remodeling complex, disassociation of SF1 and Sp1, retaining of TR2, recruitment of receptor‐interaction protein 140, G9a and HP1γ, and sequential insertion of two nucleosomes on CR1 that progressively displays repressive heterochromatin marks. This study demonstrates a functional role for Pml in maintaining a specific open chromatin conformation of the Oct4 promoter region for its constant expression in stem cells; and illustrates the mechanism underlying RA‐induced chromatin remodeling of Oct4 gene in differentiating cells, in which Pml plays a critical role. The study also demonstrates a novel mode of chromatin remodeling, which occurs by repositioning and sequentially inserting nucleosomes into a specific region of the gene promoter to compact the chromatin in differentiating cells. STEM Cells 2011;29:660–669