Abstract
The transcription factor Bcl11b is critically required to support the development of diverse cell types, including T lymphocytes, type 2 innate lymphoid cells, neurons, craniofacial mesenchyme and keratinocytes. Although in T cell development its onset of expression is tightly linked to T-lymphoid lineage commitment, the Bcl11b protein in fact regulates substantially different sets of genes in different lymphocyte populations, playing strongly context-dependent roles. Somewhat unusually for lineage-defining transcription factors with site-specific DNA binding activity, much of the reported chromatin binding of Bcl11b appears to be indirect, or guided in large part by interactions with other transcription factors. We describe evidence suggesting that a further way in which Bcl11b exerts such distinct stage-dependent functions is by nucleating changes in regional suites of epigenetic modifications through recruitment of multiple families of chromatin-modifying enzyme complexes. Herein we explore what is - and what remains to be - understood of the roles of Bcl11b, its cofactors, and how it modifies the epigenetic state of the cell to enforce its diverse set of context-specific transcriptional and developmental programs.
Highlights
The paralogous Bcl11 zinc finger transcription factors, Bcl11a and Bcl11b, were first identified in a yeast two-hybrid screen for binding partners of the COUP-TF family of nuclear hormone receptors [1]
Stage-specific binding patterns and acute Bcl11b knockout results show that Runx1 binding at numerous sites across ~150 kb encoding TCRb locus V regions only occurs when Bcl11b is present, whereas Runx1 binding across the TCRg locus occurs in the same cells whether Bcl11b is there or not [40]. This concerted effect suggests that Bcl11b must co-bind with Runx1 to promote a state switch of this extended TCRb coding region from chromatin closure to accessibility, and that this may explain the selective defect in TCRb gene rearrangement in Bcl11bdeficient cells [5]
Bcl11b is a potent factor, needed to support and repress multiple distinct cellular lineages. It can recruit a range of factors and complexes with chromatin-modifying, -remodeling and -looping activities
Summary
The paralogous Bcl11 zinc finger transcription factors, Bcl11a and Bcl11b, were first identified in a yeast two-hybrid screen for binding partners of the COUP-TF family of nuclear hormone receptors [1]. These observations indicate that Bcl11b has potent, required, ongoing roles both in activating and in repressing distinctive sets of target genes in these cell types. Bcl11b was found to bind to the known regulatory elements of the Cd4 gene, targets where it apparently exerted positive regulatory effects both for activation and for maintenance in the CD4SP lineage [36] (Figure 4, upper right).
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