Transcription initiation machinery variability and functionality during differentiation and development

Transcription initiation machinery variability and functionality during differentiation and development


Stéphane VINCENT

RNA polymerase II (Pol II) transcription initiation requires the stepwise assembly of protein complexes on core promoters forming the preinitiation complex (PIC), as a result of interactions with enhancers, transcription factors and transcriptional co-activators. A functional PIC is composed of Pol II and 6 multi-protein complexes called general transcription factors (GTFs): TFIIA, TFIIB, TFIID, TFIIE, THIIF and TFIIH. TFIID is an evolutionary conserved GTF from yeast to mammals and plays a major role in transcription initiation as it is the first GTF to initiate PIC assembly by recognizing the promoter sequences. TFIID is a large multi-protein complex composed of the TATA binding protein (TBP) and 13 TBP-associated factors (TAF1-13) in metazoans.

The traditional text-book model suggesting that transcription initiation is always regulated by the same transcription complexes has been challenged in metazoans in the last decade. First, the discovery of specialized TAFs paralogs associated with cell-type specific gene expression programs unravelled the existence of potential cell-type specific TFIID complexes. Second, analyses of mouse mutants but also of human patients highlighted the context-dependent requirement of some TAFs for transcription suggesting that partial TFIID complexes could compensate for the lack of canonical TFIID. Third, three metazoan TBP homologs have been identified based on their conservation with the characteristic horse saddle C-terminal DNA binding domain of TBP: we have recently shown that during oocyte growth TFIID is not present being replaced by a TBPL2/TFIIA oocyte-specific complex.

We are interested in the functional significance of the variability and composition of the protein complexes involved in the recognition of the core promoters in 2 axes:

  1. Functional importance of TFIID submodules in mediating transcription initiation
  2. Structure and function of the oocyte-specific transcription initiation machinery in mammals