Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1.

Yun Hsiao Lin,Poorani Ganesh Subramani,David Langlais,Michael Förster,Lin Tze Tung,Simon Clare,Javier M Di Noia,Yue Liang,Hanchen Wang,Anastasia Nijnik

doi:10.3389/fimmu.2021.626418

Abstract

BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumor suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1 fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1 fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

Highlights

B cells are mediators of the humoral immune response, with crucial roles in the defense against infections, anti-tumor immunity, allergic response, and autoimmune disorders [1,2,3]
We establish the non-redundant and cell intrinsic role of BAP1 in the normal progression of B cell development, and suggest BAP1 as a regulator of the transcriptional programs required for cell proliferation and cell cycle progression in pre-B cells, via its deubiquitinase catalytic activity for histone H2AK119ub
Bcell dysfunction was previously reported by Arenzana et al, following an inducible deletion of Bap1 in the Bap1fl/flCreERT2 mouse model [47], showing a depletion of pre-pro-B, small preB, immature, and mature B cell subsets

Summary

Introduction

B cells are mediators of the humoral immune response, with crucial roles in the defense against infections, anti-tumor immunity, allergic response, and autoimmune disorders [1,2,3]. Monoubiquitination of histone H2A (H2AK119ub) is a highly abundant histone modification, associated with gene silencing [8, 9]. It is primarily deposited on chromatin by the RING1B subunit of the Polycomb repressive complex 1 (PRC1), which acts as a major epigenetic regulator of cell identity, differentiation, and development [9,10,11]. BAP1 is becoming widely recognized as the major ubiquitously expressed DUB for histone H2A, its role in B cell development and physiology remains poorly explored

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