Diversity in TAF proteomics: consequences for cellular differentiation and migration

Abstract

Development is a highly controlled process of cell proliferation and differentiation driven by mechanisms of dynamic gene regulation. Specific DNA binding factors for establishing cell- and tissue-specific transcriptional programs have been characterised in different cell and animal models. However, much less is known about the role of "core transcription machinery" during cell differentiation, given that general transcription factors and their spatiotemporally patterned activity govern different aspects of cell function. In this review, we focus on the role of TATA-box associated factor 4 (TAF4) and its functional isoforms generated by alternative splicing in controlling lineage-specific differentiation of normal mesenchymal stem cells and cancer stem cells. In the light of our recent findings, induction, control and maintenance of cell differentiation status implies diversification of the transcription initiation apparatus orchestrated by alternative splicing.

Figure 1

Multi-subunit tissue-specific RNA Pol II preinitiation complex (PIC) at the site of transcription. The main components of basal transcription preinitiation machinery (RNA Pol II (purple), GTFs (green), and Mediator (blue)) are presented. The tentative placement of some TBP-associated factors (TAF subunits) in the canonical TFIID complex (orange) is shown. TAF4 is specifically highlighted in brown. The co-activators/co-repressors (light brown) bridge upstream DNA-bound cell-specific transcription factors (yellow) with transcription machinery. It should be noted that various PIC complexes with different subunit compositions and sequence variation (isoforms) might be present, thus further diversifying PIC architecture beyond the example shown in this figure. TF, transcription factor; TBP, TATA box-binding protein; GTFs, general transcription factors.

Figure 2

Alternative splicing of human TAF4 (NM_003185.3) leads to a variety of protein isoforms. TAF4 gene structure and major TAF4 isoforms with deletions in the co-activator-binding hTAF4–TAFH domain are outlined. Some isoforms of TAF4, for example TAF4 ASV_v2, differ in their C-terminus. Functionally important TAFH (hTAF4–TAFH, orange) and HF (Histone-fold, blue) domains are highlighted. Boundaries of hTAF4–TAFH domain are shown by amino acid residue numbers above the structures and correspond to their position in the canonical form of TAF4, where the * symbol represents deletion of the amino acids 628–658 in the TAFH domain.

Figure 3

A model describing the cross-talk between canonical TAF4 and its alternative isoforms in pluripotent (stem cells) and differentiated cells, and their relation to migration. High levels of canonical TAF4 (blue arrow from left to right) are a characteristic to normal stem cells and cancer cells. In contrast, differentiated cells maintain high expression of TAF4 isoforms with deletions in hTAF4–TAFH domain (blue arrow from right to left). Functional balance between canonical and alternative isoforms of TAF4 is crucial for cell migration. Consistent with this, cells with low expression of canonical TAF4 are prone to migration contrasting with low motility of cells with high levels of TAF4 activity.