RESUMEN
The polycistronic mir-17-92 cluster, also known as oncomir-1, was previously shown to be essential for early B lymphopoiesis. However, its role in late-stage B-cell differentiation and function remains unexplored. Here we ablate mir-17-92 in mature B cells and demonstrate that mir-17-92 is dispensable for conventional B-cell development in the periphery. Interestingly, mir-17-92-deficiency in B cells leads to enhanced homing of plasma cells to the bone marrow during T-cell-dependent immune response and selectively impairs IgG2c production. Mechanistically, mir-17-92 directly represses the expression of Sphingosine 1-phosphate receptor 1 and transcription factor IKAROS, which are, respectively, important for plasma cell homing and IgG2c production. We further show that deletion of mir-17-92 could reduce IgG2c anti-DNA autoantibody production and hence mitigate immune complex glomerulonephritis in Shp1-deficient mice prone to autoimmunity. Our results identify important roles for mir-17-92 in the regulation of peripheral B-cell function.
Asunto(s)
Linfocitos B/inmunología , Movimiento Celular/genética , Inmunoglobulina G/biosíntesis , MicroARNs/genética , Células Plasmáticas/inmunología , Animales , Anticuerpos Antinucleares/biosíntesis , Médula Ósea/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Citometría de Flujo , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Enfermedades del Complejo Inmune/genética , Enfermedades del Complejo Inmune/inmunología , Ratones , MicroARNs/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Esfingosina-1-Fosfato , Linfocitos T/inmunologíaRESUMEN
Several Sox-Oct transcription factor (TF) combinations have been shown to cooperate on diverse enhancers to determine cell fates. Here, we developed a method to quantify biochemically the Sox-Oct cooperation and assessed the pairing of the high-mobility group (HMG) domains of 11 Sox TFs with Oct4 on a series of composite DNA elements. This way, we clustered Sox proteins according to their dimerization preferences illustrating that Sox HMG domains evolved different propensities to cooperate with Oct4. Sox2, Sox14, Sox21 and Sox15 strongly cooperate on the canonical element but compete with Oct4 on a recently discovered compressed element. Sry also cooperates on the canonical element but binds additively to the compressed element. In contrast, Sox17 and Sox4 cooperate more strongly on the compressed than on the canonical element. Sox5 and Sox18 show some cooperation on both elements, whereas Sox8 and Sox9 compete on both elements. Testing rationally mutated Sox proteins combined with structural modeling highlights critical amino acids for differential Sox-Oct4 partnerships and demonstrates that the cooperativity correlates with the efficiency in producing induced pluripotent stem cells. Our results suggest selective Sox-Oct partnerships in genome regulation and provide a toolset to study protein cooperation on DNA.