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: Bright, ARID3a, hematopoietic regulation, B cell development, gene regulationBright (B cell regulator of immunoglobulin heavy chain transcription) is a 70 kDa DNA-binding protein first characterized in the mouse as a component of a protein complex associated with increased transcription of the immunoglobulin heavy chain (IgH) locus in activated B lymphocytes (1-3). Bright, also known as DRIL1, E2FBP1, or ARID3a (the designation for the human ortholog, hereafter referred to as Bright), is a member of the A + T rich interaction domain (ARID) protein family, many of which have been shown recently to have epigenetic regulatory functions [reviewed in ]. These proteins bind to A + T rich DNA sequences and are typically members of larger chromatin modulatory complexes. Bright, and other ARID3 family members, require dimerization for DNA-binding activity and contain an extended DNA-binding domain that confers increased DNA sequence specificity to these proteins compared to other ARID family members (7-9). Although Bright was the first member of this family identified in mammalian cells, its functions have only begun to be elucidated. Previously, Bright expression in adult, mouse, and human cells was thought to be largely restricted to B lymphocyte lineage cells. However, more recently, we and others have shown that Bright plays important regulatory functions in early hematopoiesis. Although Bright expression is restricted in adults, it is more widely expressed in the embryo/fetus and plays important regulatory roles in embryonic stem cell differentiation (10). These data also highlight novel roles for Bright in gene repression. This artic...

The Transcription Factor ARID3a Is Important for In Vitro Differentiation of Human Hematopoietic Progenitors

“…Because ARID3a was originally described as a B lineage-specific protein (reviewed in 3), we determined if ARID3a contributed to B lineage development. Therefore, we assessed the ability of HSPCs transduced with shRNA against ARID3a or an unrelated control shRNA to develop into B lineage cells in vitro under conditions that allow B lineage development.…”

“…ARID3a inhibition resulted in increased development of myeloid lineage cells (1, thicker arrow) versus lymphocyte lineages, and inhibited B lymphocyte lineage development without affecting natural killer (NK) cells (2). Conversely, ARID3a over-expression blocked myeloid lineage development at unidentified stages resulting in decreased maturation of erythroid (E), monocyte (M), granulocyte/monocyte (GM), granulocyte/erythroid/megakaryocyte/monocyte (GEMM) and erythroid burst blast (BFU-E) colonies (3). …”

Interferon-α signaling promotes embryonic HSC maturation

“…[59][60][61][62] Matrix-associated regions compartmentalize specific loops of chromatin and in this case, juxtapose V H promoters with Em to mediate high level transcription of the locus during development. [63][64][65] As with other members of the ARID family,…”

Chromatin and Transcriptional Tango on the Immune Dance Floor

“…The sequential involvement of transcription factors and chromatin regulators remains an open question, and Choukrallah and Matthias review our current understanding of these factors in B cell development ( 17 ). Webb and colleagues discuss the role of transcription factor Bright in both human and mouse B cell development ( 18 ), while Serfling and colleagues review the role of NFATc1 transcription factor during hematopoiesis ( 19 ).…”