The transcription factor ZEB2 drives the formation of age-associated B cells.
Dai DaiShuangshuang GuXiaxia HanHuihua DingYang JiangXiao-Ou ZhangChao YaoSoonmin HongJinsong ZhangYiwei ShenGuojun HouBo QuHaibo ZhouYuting QinYuke HeJianyang MaZhihua YinZhizhong YeJie QianQian JiangLihua WuQiang GuoSheng ChenChuan-Xin HuangLeah C KottyanMatthew T WeirauchCarola G VinuesaNan ShenPublished in: Science (New York, N.Y.) (2024)
Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b ( Mef2b )'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax . ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.
Keyphrases
- epithelial mesenchymal transition
- transcription factor
- long non coding rna
- toll like receptor
- nuclear factor
- systemic lupus erythematosus
- inflammatory response
- binding protein
- dna binding
- multiple sclerosis
- end stage renal disease
- immune response
- high fat diet induced
- chronic kidney disease
- disease activity
- endothelial cells
- rheumatoid arthritis
- ejection fraction
- newly diagnosed
- dna methylation
- prognostic factors
- genome wide identification
- patient reported outcomes
- smoking cessation
- replacement therapy