Many transcription factors regulate specific temporal-spatial events during cardiac differentiation; however, the mechanisms that regulate such events are largely unknown. Using a modified subtractive hybridization method to identify specific genes that influence early cardiac development, we found that Bop is expressed specifically in

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The m-Bop protein encoded by the mouse Bop gene is strongly expressed in heart and skeletal muscle, and recent studies with Bop knockout mice have demonstrated that m-Bop is essential for cardiogenesis in vivo and can act as a HDAC-dependent repressor in vitro. In the present studies, m-Bop was observed to interact with skNAC, a reported transcriptional activator specific to heart and skeletal muscle. The amino-terminal S region of the split S-ET domain of m-Bop as well as the MYND domain were required for interaction with skNAC in both the two-hybrid system and in coimmunoprecipitation experiments from cultured mammalian cells. As shown previously for interaction of the MYND domain-containing transcriptional corepressor, BS69, with several viral and cellular oncoproteins, a PXLXP motif in skNAC was required for interaction with mBop. Similar kinetics of induction and localization of m-Bop and skNAC during the induction of myogenesis in cultured C2C12 cells suggests a possible associated role for these proteins during this process.The control of skeletal and cardiac maturation is ordered in a complex cascade of transcriptional activation and repression. The MyoD and MEF2 families of transcription factors dictate important developmental events that result in the formation of mature skeletal muscle. The MyoD family is comprised of the basic helix-loop-helix proteins MyoD, Myf5, MRF4, and myogenin. These myogenic regulators form heterodimers with the ubiquitous basic helix-loop-helix E proteins that subsequently activate key elements needed for the myogenic program (1). The MEF2 family is defined by the MADS domain and consists of MEF2A, MEF2B, MEF2C, and MEF2D. Members of the MEF2 family are expressed in tissues besides skeletal muscle including cardiac tissue, neurons, and T cells (2). Together, the MyoD and MEF2 families cooperate directly and indirectly to transduce the requisite signals for proper skeletal muscle formation.The discovery of chamber-specific transcription factors, such as the Hand1 and Hand2 proteins, has revealed the complex nature of cardiac transcriptional regulation (3). The list of genes that correspond to specific cardiac defects continues to grow, whereas the molecular nature of these defects remains largely elusive (4). To further understand the molecular underpinnings of cardiac development, it is critical to identify the relationships of transcriptional regulators shown to be important in cardiac morphogenesis.The Bop gene encodes distinct proteins expressed in skeletal and cardiac muscle, as well as in cytotoxic T lymphocytes. The Bop proteins found in skeletal muscle (m-Bop) and cytotoxic T lymphocytes (t-Bop) are identical over 90% of their primary amino acid sequence, differing only at their extreme amino terminus (5). Bop contains the evolutionarily conserved MYND and SET domains found in transcriptional regulators linked to development, chromatin stability, and cancer. The MYND domains in the transcriptional regulators ETO (MTG8) and BS69 function as protein-protein interaction d...

Bright/Arid3a has been characterized both as an activator of immunoglobulin heavy-chain transcription and as a proto-oncogene. Although Bright expression is highly B lineage stage restricted in adult mice, its expression in the earliest identifiable hematopoietic stem cell (HSC) population suggests that Bright might have additional functions. We showed that >99% of Bright ؊/؊ embryos die at midgestation from failed hematopoiesis. Bright ؊/؊ embryonic day 12.5 (E12.5) fetal livers showed an increase in the expression of immature markers. Colony-forming assays indicated that the hematopoietic potential of Bright ؊/؊ mice is markedly reduced. Rare survivors of lethality, which were not compensated by the closely related paralogue Bright-derived protein (Bdp)/Arid3b, suffered HSC deficits in their bone marrow as well as B lineage-intrinsic developmental and functional deficiencies in their peripheries. These include a reduction in a natural antibody, B-1 responses to phosphocholine, and selective T-dependent impairment of IgG1 class switching. Our results place Bright/Arid3a on a select list of transcriptional regulators required to program both HSC and lineage-specific differentiation.The formation and maintenance of blood throughout fetal and adult life rely on the self-renewal of hematopoietic stem cells (HSCs). Rare HSCs arise in the embryonic yolk sac and aorta-gonad mesonephros AGM, seed the fetal liver, and then circulate in the bone marrow of adult mammals. Fetal and adult HSC progenitors become progressively dedicated to differentiation into erythrocytes, myeloid cells, and lymphocytes. Transcription factors critical for the specification and formation of HSCs cover a wide range of DNA binding protein families. An emerging theme is that many of these same regulators are required later for the differentiation of individual blood lineages, which explains why a number of HSC transcription factors were discovered and originally characterized because of their deregulation in hematopoietic malignancies.Bright/Arid3a/Dril1 is the founder of the AT-rich interaction domain (ARID) superfamily of DNA binding proteins (18,60). Bright, in a complex with Bruton's tyrosine kinase (Btk) and TFII-I, binds to specific AT-rich motifs within the nuclearmatrix attachment regions (MARs) of the immunoglobulin heavy-chain (IgH) intronic enhancer (E) and selected IgH promoters to activate IgH transcription (18,25,30,43,44,55,57,58). B cell-specific, transgenic overexpression of Bright leads to partial blocks at both the late-pre-B and T1 immature stages, skewed marginal-zone (MZ) B cell development, increased natural IgM antibody production, and intrinsic autoimmunity (49). Transgenic dominant negative (DN) inhibition of Bright DNA binding results in reduced levels of IgM in serum and functional perturbation of IgM secretion by B-1 cells (39,48). A small pool of Bright cycles from the nucleus into plasma membrane lipid rafts, where it associates with Btk to dampen antigen receptor signaling (48).While highly B lineage restricted in...