Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2) modulate chromatin accessibility through covalent histone modifications. The ubiquitous expression of PRC1 catalytic subunits throughout B cell development hypothesized roles for PRC1 in B cell physiology. This study aimed to dissect the contribution of PRC1 to peripheral B cell maturation, homeostasis and terminal differentiation. We analyzed mutant mice allowing conditional Cre-dependent inactivation of PRC1 catalytic function starting from late transitional B cells. In response to induced PRC1 inactivation, peripheral B cells in secondary lymphoid organs were reduced in number and displayed alterations in the surface phenotype, which reflected a major disturbance of their transcriptional profile. Reduced fitness of PRC1 mutant resting B cells was associated to heightened sensitivity to pro-apoptotic signals, consequent of the higher levels in these cells of the BIM protein and of the sub-optimal activation of the AKT kinase in response to either BAFF-R or BCR engagement. PRC1 mutant mice displayed major defects in the marginal zone (MZ) B cell subset, both in number and localization. This phenotype correlated with reduced expression of the Sphingosine-1-phosphate receptor-1 (S1pr1), which is crucial for B cell migration to the MZ, and the increased expression of the Polycomb target microRNA mir-125b, which targets S1pr1 transcript. Moreover, PRC1 mutant B cells displayed premature de-repression of Prdm1 gene and facilitated plasma cell differentiation upon lipopolysaccharide stimulation. Our work provides evidence for a crucial role played by PRC1 in peripheral B cell subset differentiation, B cell homeostasis and timing of terminal B cell differentiation.
|Titolo:||POLYCOMB GROUP PROTEINS RING1A/RING1B CONTROL PERIPHERAL B CELL HOMEOSTASIS AND TERMINAL DIFFERENTIATION|
|Tutor esterno:||CASOLA, STEFANO|
|Data di pubblicazione:||28-gen-2019|
|Parole Chiave:||Polycomb Repressive Complexes; PRC1; B cell development; B cell homeostasis; B cell differentiation; epigenetics; miRNA; alternative splicing|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Citazione:||POLYCOMB GROUP PROTEINS RING1A/RING1B CONTROL PERIPHERAL B CELL HOMEOSTASIS AND TERMINAL DIFFERENTIATION / F. La Mastra ; internal advisor: Diego Pasini ; supervisor: S. Casola. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018.|
|Appare nelle tipologie:||Tesi di dottorato|