Abstract
Bcor (BCL6 corepressor) is a widely expressed gene that is mutated in patients with X-linked Oculofaciocardiodental (OFCD) syndrome. BCOR regulates gene expression in association with a complex of proteins capable of epigenetic modification of chromatin. These include Polycomb group (PcG) proteins, Skp-Cullin-F-box (SCF) ubiquitin ligase components and a Jumonji C (Jmjc) domain containing histone demethylase. To model OFCD in mice and dissect the role of Bcor in development we have characterized two loss of function Bcor alleles. We find that Bcor loss of function results in a strong parent-of-origin effect, most likely indicating a requirement for Bcor in extraembryonic development. Using Bcor loss of function embryonic stem (ES) cells and in vitro differentiation assays, we demonstrate that Bcor plays a role in the regulation of gene expression very early in the differentiation of ES cells into ectoderm, mesoderm and downstream hematopoietic lineages. Normal expression of affected genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury and Flk1) is restored upon re-expression of Bcor. Consistent with these ES cell results, chimeric animals generated with the same loss of function Bcor alleles show a low contribution to B and T cells and erythrocytes and have kinked and shortened tails, consistent with reduced Brachyury expression. Together these results suggest that Bcor plays a role in differentiation of multiple tissue lineages during early embryonic development.
Highlights
Mutations causing gene fusions, loss of function or misregulation of transcriptional corepressor proteins have been implicated both in genetically inherited diseases and cancer [1,2]
In cell lines derived from such patients, BCOR is detected at a number of BCL6 target genes suggesting that BCOR is likely to play a role in mediating BCL6 driven lymphomagenesis
Generation and analysis of a conditional Bcor allele To investigate the role of the X-linked Bcor gene in development, we generated a conditional Bcor allele, BcorFl, in which exon 3 is flanked by loxP sites to allow its removal via expression of Cre recombinase (Figure 1A and targeting verification Figure 1B)
Summary
Loss of function or misregulation of transcriptional corepressor proteins have been implicated both in genetically inherited diseases and cancer [1,2]. BCOR (BCL6 corepressor) is a transcriptional corepressor that was originally identified by its ability to interact with the site specific transcriptional repressor BCL6 [3]. BCL6 plays critical roles in specific immunological processes involving B and T cells, including germinal center formation and the generation and maintenance of memory T cells [6,7,8,9,10]. In cell lines derived from such patients, BCOR is detected at a number of BCL6 target genes suggesting that BCOR is likely to play a role in mediating BCL6 driven lymphomagenesis. BCOR has been shown to directly interact with the transcriptional regulator
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