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.
POLYCOMB GROUP PROTEINS RING1A/RING1B CONTROL PERIPHERAL B CELL HOMEOSTASIS AND TERMINAL DIFFERENTIATION / F. La Mastra ; internal advisor: Diego Pasini ; supervisor: S. Casola. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2019 Jan 28. 30. ciclo, Anno Accademico 2018. [10.13130/la-mastra-federica_phd2019-01-28].
POLYCOMB GROUP PROTEINS RING1A/RING1B CONTROL PERIPHERAL B CELL HOMEOSTASIS AND TERMINAL DIFFERENTIATION
F. LA MASTRA
2019
Abstract
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.File | Dimensione | Formato | |
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