Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis

Abstract

Polycomb chromatin modifiers regulate hematopoietic pluripotent stem and progenitor cell self-renewal and expansion. Polycomb complex redundancy and biochemical heterogeneity complicate the unraveling of the functional contributions of distinct components. We have studied the hematopoietic activity of RYBP, a direct interactor and proposed modulator of RING1A/RING1B-dependent histone H2A monoubiquitylation (H2AUb). Using a mouse model to conditionally inactivate Rybp in adult hematopoiesis, we have found that RYBP deletion results in a reversion of B-1-to-B-2 B-cell progenitor ratios, i.e., of the innate (predominantly fetal) to acquired (mostly adult) immunity precursors. Increased numbers of B-1 progenitors correlated with a loss of pre-proB cells, the B-2 progenitors. RYBP-deficient stem and progenitor cell populations (LKS) and isolated common lymphoid progenitors (CLP) gave rise to increased numbers of B-1 progenitors in vitro. Rybp inactivation, however, did not result in changes of global H2AUb and did not interact genetically with Ring1A or Ring1B deletions. These results show that a sustained regulation of the B-1-to-B-2 switch is needed throughout adult life and that RYBP plays an important role in keeping B-2 dominance, most likely independently of its Polycomb affiliation.

ACKNOWLEDGMENTS

We are grateful to K. Dorshkind (UCLA) for S17 stromal cells, to M. Barbacid and M. Serrano (CNIO) for Polr2a::Cre-ER^T2 and Ink4a mutant mice, respectively, and to Laura Molero, head of the UAM SIdI Flow Cytometry facility, for help with data analysis and cell sorting.

K.S. and M.B. are supported by FP7-PEOPLE-2011-ITN, grant 289611, and a MINECO fellowship. This work was supported by grants BFU2008-03386/BMC (MINECO) to C.C., BFU2010-18146, SAF2013-47997-P (MINECO), and the CAM OncoCycle Program (S2010/BMD-2470) to M.V.