HOXA1 and the post-translational modifiers OGT and PRDM14

Hox genes encode transcription factors which are well described for their implication during animal embryogenesis. In particular HOXA1 is involved in patterning the hindbrain and somitic derivatives as well as in inner ear and heart development. While the functions of HOXA1 are well known, the mode of action of this protein has been poorly characterised. In that context, a proteome-wide screening to identify proteins interacting with HOXA1 has been carried out in our laboratory and revealed OGT and PRDM14 as potential modulators of HOXA1 function. OGT is the only known mammalian enzyme able to add an O-GlcNAc group on target proteins. O-GlcNAcylation is involved in a variety of cellular processes from gene transcription to protein degradation. PRDM14 belongs to the PRDM family of proteins described to be histone methyltransferases. PRDM14 is involved in the maintenance of cell pluripotency and modulates the epigenetic landscape of target genes. Significantly to HOXA1 activity, both OGT and PRDM14 have also been described to be co-regulators of transcription. The goal of our thesis was therefore to characterize the modalities and the possible consequences of the interaction between HOXA1 and these two partners, OGT and PRDM14. At the molecular level, we showed that the N-terminal part of HOXA1 is required for its interaction with OGT while it is its homeodomain and a 11-His repeat motif which are necessary for its binding to PRDM14. On the other side, the TPR domain of OGT and the PR and zinc fingers domains of PRDM14 are required to interact with HOXA1. Next, we demonstrated that HOXA1 can be O-GlcNAcylated and phosphorylated and that the abundance of these modifications is dependent on the presence of OGT. However, the molecular consequences of HOXA1 O-GlcNAcylation still need to be identified. We also observed that PRDM14 can impact the transcriptional activity of HOXA1 and that this seems to be associated with a decrease of its stability. Finally, we overviewed what has been reported to date about the regulation of HOX protein activities by post-translational modifications (PTMs). The importance of PTMs on HOX function is expected to be by far under evaluated, supporting that further investigations on partners of HOX proteins are needed to decipher their molecular regulations.