Regulatory gene network circuits underlying T cell development from multipotent progenitors

Abstract

Regulatory gene circuits enable stem and progenitor cells to detect and process developmental signals and make irreversible fate commitment decisions. To gain insight into the gene circuits underlying the T-cell specification decision in progenitor cells, we generated an updated T lymphocyte developmental gene regulatory network from genes and connections found in the literature. This reconstruction allowed us to identify candidate regulatory gene circuit elements underlying T-cell fate decision making. Here, we examine the roles of these circuits in facilitating different aspects of the decision making process, and discuss experiments to further probe their structure and function.

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

“…Immature T-ALL/ETP-ALL and outcome haematologica | 2014; 99 (1)Consistent with this hypothesis, the gene signature of our immature cluster 6 (Online Supplementary Table S5) was significantly enriched for genes (probe sets) that are expressed in sorted hematopoietic stem cells, early erythroid precursor cells, and B-cell fractions as established by Novershtern and co-workers 37 (Online Supplementary Table S6). Remarkably, genes that are typically down-regulated during normal T-cell development were enriched in cases with the immature cluster signature.…”

Notch Signaling During Human T cell Development

“…While the role of differential Notch receptor/ligands remains to be explored, also the integration of various molecular mechanisms downstream of the Notch receptors into the global transcriptional network that drives human T cell development is still in its infancy. While much more progress has been made with respect to these issues in the mouse (Kueh and Rothenberg, 2012;Radtke et al, 2010;Maillard et al, 2005;Yuan et al, 2010), we anticipate that novel technical advances, that enable for instance knockout and genereporter approaches in human ES cells, will yield more definitive in-sights into these processes (Timmermans et al, 2009;Galic et al, 2006;Hockemeyer et al, 2009;Hockemeyer et al, 2011). Given that recent insights suggest important regulatory differences for the Notch signaling pathway in human versus mouse T-acute lymphoblastic leukemia , tackling these questions is of vital importance for understanding normal and malignant developmental processes in human.…”

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

“…A model for the GRN that guides T-cell commitment has been assembled over the last decade (18,19) but new linkages that control aspects of commitment timing have now been illuminated. Recent reports have identified key mechanisms that make the transition from precommitment to commitment into such a discontinuous, switch-like event.…”

“…In fact, many of the new Bcl11b target genes are unique to the pericommitment developmental context. We place these findings in the context of an updated version of the T-cell specification GRN model (5,(18)(19)(20) enhanced with recent insights into connections between PU.1, Bcl11b, Notch signaling, and other crucial factors: that is, GATA-3, TCF-1, Runx1, and the basic helixloop-helix factor E2A.…”