Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Abstract

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

Cytokines, Transcription Factors, and the Initiation of T-Cell Development

“…ILCs keep the Rag genes off, at least in part because of neutralization of E protein activity by Id2 (Diefenbach et al 2014; De Obaldia and Bhandoola 2015; Serafini et al 2015). In contrast, high levels of BCL11B, exceeding those in any ILC subset, restrain Id2 expression in cells taking the T-cell pathway (Longabaugh et al 2017). …”

“…DN2b cells proliferate more slowly than DN2a, and their survival becomes strictly Notch-dependent (Yui et al 2010). It is still not certain whether BCL11B directly represses most phase 1 regulatory genes or simply disables signaling that would otherwise maintain their expression (Longabaugh et al 2017), but in either case its action allows most phase 1-restricted genes to be silenced and enables the cells to enter a committed DN2b state (Ikawa et al 2010; Li et al 2010a; Li et al 2010b)).…”

“…E proteins are required to promote and sustain NOTCH1 expression in DN3a stage and Notch signaling can be antagonized by the E protein antagonist Id2. BCL11B at a high level keeps Id2 expression silent and assists activation of Dntt and the Cd3 gene cluster (Longabaugh et al 2017), to support transition to the DN3a state. Thus, most of the T cell genes are fully activated, and cell cycle arrest is induced by late Phase 2 stage.…”

Non-coding Transcription Instructs Chromatin Folding and Compartmentalization to Dictate Enhancer-Promoter Communication and T Cell Fate

“…Specifically, Bcl11b expression is initiated at the DN2a cell stage to promote developmental progression to the DN2b cell stage. At the DN2b cell stage Bcl11b expression is further elevated and in concert with E2A activates a T-lineage specific program of gene expression and suppresses the expression of genes associated with alternative cell fates (Liu et al, 2010; Ikawa et al, 2010; Li et al, 2011; Longabaugh et al, 2017). The activation of Bcl11b expression in DN2 cells involves Notch signaling, GATA-3, TCF1 and RUNX1 that bind to an enhancer, named Major Peak, located in the Bcl11b intergenic locus control region (Guo et al, 2008; Weber et al, 2013; Garcia-Ojedo et al, 2013; Li et al, 2013).…”

Gene regulatory networks and network models in development and evolution

“…One thing that is clear from the papers that follow is that the impact of thinking on gene networks in bioscience is truly broad and deep. The topics span a wide range, from the differentiation of germ cells (1), immunology (2,3), and the molecular basis of celltype differentiation (4)(5)(6)(7)(8)(9)(10)(11), to paleontology (12,13) and behavior (14). The central role of network thinking is revealed in the way it allows for both the design of testable experimental frameworks to probe complex biological processes and the conceptual framework for understanding biological mechanisms.…”