Logic and lineage impacts on functional transcription factor deployment for T-cell fate commitment

Abstract

Transcription factors are the major agents that read the regulatory sequence information in the genome to initiate changes in expression of specific genes, both in development and in physiological activation responses. Their actions depend on site-specific DNA binding and are largely guided by their individual DNA target sequence specificities. However, their action is far more conditional in a real developmental context than would be expected for simple reading of local genomic DNA sequence, which is common to all cells in the organism. They are constrained by slow-changing chromatin states and by interactions with other transcription factors, which affect their occupancy patterns of potential sites across the genome. These mechanisms lead to emergent discontinuities in function even for transcription factors with minimally changing expression. This is well revealed by diverse lineages of blood cells developing throughout life from hematopoietic stem cells, which use overlapping combinations of transcription factors to drive strongly divergent gene regulation programs. Here, using development of T lymphocytes from hematopoietic multipotent progenitor cells as a focus, recent evidence is reviewed on how binding specificity and dynamics, transcription factor cooperativity, and chromatin state changes impact the effective regulatory functions of key transcription factors including PU.1, Runx1, Notch-RBPJ, and Bcl11b.

The unique function of Runx1 in skeletal muscle differentiation and regeneration is mediated by an ETS interaction domain

“…Runx1 has been extensively investigated for its role in T cell development, where it is co-expressed with Runx3 , and in muscle development, where it is co-expressed with Runx2 . Similar to its multiple roles supporting the common lymphocyte progenitors through their subsequent differentiation to T and B cell linages in adult hematopoiesis (Growney et al, 2005; Rothenberg, 2021; Shin et al, 2021), we show here that in addition of an established role in the adult skeletal muscle response to injury, Runx1 is also involved in SC maintenance in the absence of injury.…”

Dynamic chromatin accessibility deploys heterotypic cis/trans-acting factors driving stomatal cell-fate commitment

“…Such heterotypic TF complex is also observed during cardiogenesis, hematopoiesis and myogenesis 9 , 55 – 59 . For instance, heterotypic TF interactions among the T-box TF TBX5, the homoeodomain TF NKX2-5 and the zinc finger TF GATA4 not only coordinate cardiac gene expression, differentiation and morphogenesis, but also mutually limit their potential from binding to developmentally irrelevant regulatory elements in a given context 9 , 55 .…”

Runx factors launch T-cell and innate lymphoid programs via direct and gene network-based mechanisms

“…Profound changes occur in chromatin looping, accessibility, and histone modification profiles during T-lineage commitment [22][23][24] , associated with repression of the genes associated with progenitor and alternative lineage states and activation of the T cell identity programs 20,21,28,29 . Multiple TFs also change activity 21,30,31 . Runx TFs themselves can interact physically with multiple TFs at distinct binding sites, suggesting that TF cooperativity could be a major influence on Runx activity 13,32,33 .…”