Gfap and Osmr regulation by BRG1 and STAT3 via interchromosomal gene clustering in astrocytes

Long-range chromatin interactions between gene loci in the cell nucleus are important for many biological processes, including transcriptional regulation. Previously, we demonstrated that several genes specifically cluster with the astrocyte-specific gene for glial fibrillary acidic protein (Gfap) during astrocyte differentiation; however, the molecular mechanisms for gene clustering remain largely unknown. Here we show that brahma-related gene 1 (BRG1), an ATP-dependent chromatin remodeling factor, and the transcription factor STAT3 are required for Gfap and oncostatin M receptor (Osmr) clustering and enhanced expression through recruitment to STAT3 recognition sequences and that gene clustering occurs prior to transcriptional up-regulation. BRG1 knockdown and JAK-STAT signaling inhibition impaired clustering, leading to transcriptional down-regulation of both genes. BRG1 and STAT3 were recruited to the same Gfap fragment; JAK-STAT signaling inhibition impaired BRG1 recruitment. Our results suggest that BRG1 and STAT3 coordinately regulate gene clustering and up-regulate Gfap and Osmr transcription.