Figure 2. Understanding the fundamental molecular functions of TCF-1.

TCF-1 has multiple molecular functions that are superimposed on its’ ability to bend the DNA upon binding and regulate the 3D chromatin conformation.

(a) In the absence of β-catenin, TCF-1 can bind with the repressors of the Grg/TLE family at a region proximal to the HMG DNA binding domain ^6,97 to reduce chromatin accessibility, and suppress gene transcription ⁹⁸. Extracellular Wnts stabilize β-catenin by disrupting its’ degradatioin complex, allowing its’ nuclear translocation and interaction with the full-length TCF-1 protein. This results in the recruitment of epigenetic and transcription regulators that enhance chromatin accessibility and gene transcription. (b) TCF-1 cooperates with other transcription factors to establish context and developmental stage-specific epigenetic and transcription profiles through co-binding to common DNA sites. (c) TCF-1 could function as a pioneer-like factor and initiates changes in the chromatin landscape that establish the T cell lineage identity¹⁰¹. (d,e) TCF-1 may function as a “Place Holder”, to promote/maintain T cell-specific chromatin accessibility, independently of Wnt signals. (f) TCF-1 has intrinsic histone deacetylase activity (HDAC) and can directly reduce chromatin accessibility.