Good news! Amazing stuff!
"... Researchers ... have now discovered a molecular mechanism that helps macrophages mount a coordinated response tailored to a specific immune challenge.
Activating macrophages requires the work of three versions of a protein complex called SWI/SNF: cBAF, ncBAF, and PBAF. Scientists already knew these variants had slightly different structures, but the new findings reveal that these differences have real functional consequences ... researchers discovered that each variant plays a distinct role in initiating macrophages’ responses to intruders and, consequently, how the immune system regulates inflammation. ...
“This is a major leap in our understanding of how immune systems respond with such a high level of specificity.” ...
“This is a major leap in our understanding of how immune systems respond with such a high level of specificity.” ...
When confronted with a bacterial threat, each of the three SWI/SNF variants regulated distinct portions of the macrophages’ DNA, producing distinct cellular responses. cBAF remodeled chromatin to promote inflammation, while ncBAF modified histones to stimulate an antiviral response. PBAF also modified histones, but the result of those modifications was less clear than cBAF or ncBAF. The three acted distinctly and cooperatively to coordinate a complicated immune response that calls on the rest of the immune system to effectively and efficiently rid the body of threats. ..."
From the highlights and abstract:
"Highlights
• Inflammatory stimulation induces changes in chromatin accessibility
• SWI/SNF complex variants are cooperatively recruited to de novo enhancers
• Functional diversity among SWI/SNF variants instructs inflammatory response
• SWI/SNF inhibition disrupts de novo enhancer activation and induced gene expression
Summary
Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex—cBAF, ncBAF, and PBAF—in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting."
Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes (no public access)
Graphical abstract
No comments:
Post a Comment