T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling

Abstract

Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA-binding protein T-cell factor 1 (Tcf-1), a T-cellspecific mediator of Wnt signaling. However, the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate and show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor stage. The global expression profile of Tcf-1-deficient progenitors indicates that basic processes of DNA metabolism are down-regulated in its absence, and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the roadmap of T-cell development.

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…Induction of TCF-1 and GATA-3 promotes survival and proliferation of early double-negative T-cell precursors (DN1 and DN2) (Germar et al 2011;Weber et al 2011). NOTCH1 signaling, TCF-1, GATA-3, and RUNX1, working together at the DN2 stage, up-regulate BCL11B, which further restricts differentiation into the αβ T-cell lineage (Ikawa et al 2010;Kueh et al 2016).…”

Transcriptional regulation of the Ikzf1 locus

“…Transcription factors with putative binding sites in the Ikzf1 regulatory elements were further evaluated by analysis of ChIP-seq data at the Ikzf1 locus 17,19,31 ( Figure 7A). Many of the lymphoid lineage pioneering factors such as Ikaros, HEB, Runx1, and TCF-1 bound at multiple sites in the Ikzf1 locus.…”

β-Catenin induces T-cell transformation by promoting genomic instability

“…The T-cell-specific TCF/LEF factor Tcf-1 (product of the Tcf7 gene), one of the earliest transcriptional regulators induced in thymus seeding T-cell progenitors, is essential for T-cell commitment (13,14). Tcf-1 constitutively interacts with DNA and is thought to mediate activation of transcription when bound by β-catenin and repression when bound by Groucho.…”