BCL6 Canalizes Notch-Dependent Transcription, Excluding Mastermind-like1 from Selected Target Genes during Left-Right Patterning

Although the Notch signaling pathway is one of the most intensely studied intracellular signaling pathways, the mechanisms by which Notch signaling regulates transcription remain incompletely understood. Here, we report that B cell leukemia/lymphoma 6 (BCL6), a transcriptional repressor, is a Notch-associated factor. BCL6 is necessary to maintain the expression of Pitx2 in the left lateral plate mesoderm during the patterning of left-right asymmetry in Xenopus embryos. For this process, BCL6 forms a complex with BCL6 corepressor (BCoR) on the promoters of selected Notch target genes such as enhancer of split related 1. BCL6 also inhibits the transcription of these genes by competing for the Notch1 intracellular domain, preventing the coactivator Mastermind-like1 (MAM1) from binding. These results define a mechanism restricting Notch-activated transcription to cell-type-appropriate subsets of target genes, and elucidate its relevance in vivo during left-right asymmetric development. [Display omitted] ► BCL6 constrains Notch-driven transcription during left-right patterning ► BCL6 competes with Mastermind-like1 for Notch1 on selected Notch target genes ► Repression of Notch targets allows BCL6 to maintain left-specific gene expression.