The Histone Demethylase LSD1 Regulates B Cell Proliferation and Plasmablast Differentiation.
Robert R HainesBenjamin G BarwickChristopher D ScharerParimal MajumderTroy D RandallJeremy M BossPublished in: Journal of immunology (Baltimore, Md. : 1950) (2018)
B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM. LSD1-deficient PB exhibited derepression and superinduction of genes involved in immune system processes; a subset of these being direct Blimp-1 target-repressed genes. Cell cycle genes were globally downregulated without LSD1, which corresponded to a decrease in the proliferative capacity of LSD1-deficient activated B cells. PB lacking LSD1 displayed increased histone H3 lysine 4 monomethylation and chromatin accessibility at nB active enhancers and the binding sites of transcription factors Blimp-1, PU.1, and IRF4 that mapped to LSD1-repressed genes. Together, these data show that LSD1 is required for normal in vivo PB formation, distinguish LSD1 as a transcriptional rheostat and epigenetic modifier of B cell differentiation, and identify LSD1 as a factor responsible for decommissioning nB active enhancers.
Keyphrases
- transcription factor
- cell cycle
- cell proliferation
- heavy metals
- dna methylation
- gene expression
- genome wide
- immune response
- inflammatory response
- dendritic cells
- induced apoptosis
- cell death
- risk assessment
- nlrp inflammasome
- oxidative stress
- deep learning
- electronic health record
- anti inflammatory
- heat stress
- heat shock protein