The Bright Side of Hematopoiesis: Regulatory Roles of ARID3a/Bright in Human and Mouse Hematopoiesis

Abstract

ARID3a/Bright is a DNA-binding protein that was originally discovered for its ability to increase immunoglobulin transcription in antigen-activated B cells. It interacts with DNA as a dimer through its ARID, or A/T-rich interacting domain. In association with other proteins, ARID3a increased transcription of the immunoglobulin heavy chain and led to improved chromatin accessibility of the heavy chain enhancer. Constitutive expression of ARID3a in B lineage cells resulted in autoantibody production, suggesting its regulation is important. Abnormal ARID3a expression has also been associated with increased proliferative capacity and malignancy. Roles for ARID3a in addition to interactions with the immunoglobulin locus were suggested by transgenic and knockout mouse models. Over-expression of ARID3a resulted in skewing of mature B cell subsets and altered gene expression patterns of follicular B cells, whereas loss of function resulted in loss of B1 lineage B cells and defects in hematopoiesis. More recent studies showed that loss of ARID3a in adult somatic cells promoted developmental plasticity, alterations in gene expression patterns, and lineage fate decisions. Together, these data suggest new regulatory roles for ARID3a. The genes influenced by ARID3a are likely to play pivotal roles in lineage decisions, highlighting the importance of this understudied transcription factor.

Keywords: ARID3a; B cell development; Bright; gene regulation; hematopoietic regulation.

Figure 1

Bright expression in hematopoiesis. Hematopoietic progenitor populations [as described (11)] indicate stages, which express Bright/ARID3a (red font) versus those not known to express Bright (black font). Thick red arrows indicate stages of developmental progression for which Bright function is important. HSC, hematopoietic stem cell; MPP, multipotent progenitor; LMPP, lymphoid-primed multipotent progenitor; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; GMP, granulocyte-macrophage progenitor; MEP, megakaryocyte–erythrocyte progenitor; BCP, B cell progenitor; TCP, T cell progenitor; NKP, NK cell progenitor; MP, macrophage progenitor; GP, granulocyte progenitor; EP, erythrocyte progenitor; MkP, megakaryocyte progenitor; BAS, basophils; NE, neutrophils; MC, mast cells; EOS, eosinophils.

Figure 2

Bright expression during B lymphopoiesis. Gray cells indicate B lineage subsets not known to express Bright. Purple subsets express Bright, while lighter shades (T2, MZ B, and B1 B) represent slightly lower levels of Bright expression. Bright is required for development of B1 B cells indicated by red hash marks. Bolded arrow indicates developmental skewing caused by Bright over-expression. CLP, common lymphoid progenitor; MZ B, marginal zone B cells; FO B, follicular B cell; GC B, germinal center B cells.

Figure 3

Bright binds to sequences flanking the mouse and human IgH enhancer. Schematic diagrams of fragments including the Eμ core enhancer show binding site for E proteins, Ets proteins (μA, μB, HE2), and Oct transcription factors. Matrix association regions (MARs) identified by MAR-binding assays are indicated by red stars on either side of the core (1). Orange enhancer elements denote those regions that are not conserved between species.