Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/27/2006
Publication Date: 11/1/2006
Citation: Cai, S., Lee, C.C., Kohwi-Shigematsu, T. 2006. Satb1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nature Genetics. (38):1278-1288
Interpretive Summary: All types of enzyme expression require the initial transcription of the corresponding gene. Increasing our understanding of the fundamental mechanisms by which gene transcription is regulated has significant ramifications on any research that involves enzyme production. Transcription modulation by local DNA sequence elements, such as enhancers and operators, has been studied for decades. This paper describes the mechanism by which genes are regulated by elements which are located far away at the chromatin level.
Technical Abstract: SATB1 (special AT-rich sequence binding protein 1) organizes cell type–specific nuclear architecture by anchoring specialized DNA sequences and recruiting chromatin remodeling factors to control gene transcription. We studied the role of SATB1 in regulating the coordinated expression of Il5, Il4 and Il13, located in the 200-kb T-helper 2 (TH2) cytokine locus on mouse chromosome 11. We show that on TH2 cell activation, SATB1 expression is rapidly induced to form a unique transcriptionally active chromatin structure at the cytokine locus. In this structure, chromatin is folded into numerous small loops, all anchored to SATB1 at their base. In addition, histone H3 is acetylated at Lys9 and Lys14, and the TH2-specific factors GATA3, STAT6 and c-Maf, the chromatin-remodeling enzyme Brg1 and RNA polymerase II are all bound across the 200-kb region. Before activation, the TH2 cytokine locus is already associated with GATA3 and STAT6, showing some looping, but these are insufficient to induce cytokine gene expression. Using RNA interference, we show that on cell activation, SATB1 is required not only for compacting chromatin into dense loops at the 200-kb cytokine locus but also for inducing Il4, Il5, Il13 and c-Maf expression. Thus, SATB1 is a necessary determinant for the hitherto unidentified higher-order, transcriptionally active chromatin structure that forms on TH2 cell activation.