LIBST - Soutenance publique de thèse - Noémie DENEYER

Activity regulation of the HOXA2 transcription factor: involvement of protein interactions, post-translational modifications and intra-cellular relocation

HOX proteins are homeodomain transcription factors mainly known for their implications in animal embryogenesis. While their functions have been well documented, the molecular mechanisms regulating HOX protein activity remain scarcely characterized. To identify proteins susceptible to modulate HOX activity, our group has proceeded with interactomic screenings focusing on two proteins among which HOXA2. This allowed to reveal that the transcriptional activity of HOXA2 can be regulated by its cytoplasmic relocation mediated by the ubiquitination-promoting protein KPC2.

Here, we found out that HOXA2 can interact with three novel proteins involved in transcription factor activity modulation, namely the phosphatase PPP1CB, the kinase MSK1 and the chromodomain DNA-binding CHD4.

At the functional level, our data support a novel regulatory model according to which PPP1CB increases the nuclear export of HOXA2 initiated by KPC2. This export is correlated with a decrease in HOXA2 transcriptional activity. Once in the cytoplasm, both PPP1CB and KPC2 act together to de-ubiquitinate HOXA2 and stabilize the protein. PPP1CB and KPC2 would therefore contribute to establish a cytoplasmic store of HOXA2 in a way to modulate HOXA2 activity. This activity regulation model including post-translational modifications and subcellular relocation had not been highlighted before for a HOX protein.

About the HOXA2-CHD4 interaction, we observed that CHD4 can also decrease the HOXA2 transcriptional activity in vitro. However, while our data support that CHD4 could bind to target loci shared with HOXA2 in mouse embryos, the possible involvement of CHD4 in HOXA2 target gene selection and regulation requires additional investigation. Similarly, although the MSK1 kinase is known to target transcription factors, we failed to observe a direct effect of MSK1 toward HOXA2 behavior in vitro.

Jury members :

• Prof. René Rezsohazy (UCLouvain), supervisor
• Prof. Isabelle Donnay (UCLouvain), chairperson
• Prof. Françoise Gofflot (UCLouvain), secretary
• Prof. Pierre Morsomme (UCLouvain)
• Prof. Nicoletta Bobola (University of Manchester, UK)
• Prof. Franck Dequiedt (Université de Liège, Belgium)

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