Our team focuses on the study of ovarian development and function through molecular genetics. Our research is carried out through the molecular analysis of different pathologies such as the blepharophimosis syndrome, premature ovarian insufficiency (POI) or granulosa cell tumors, affecting one of the somatic cell types of the ovary. One of the historical topics of the group is the analysis of the blepharophimosis syndrome, involving craniofacial anomalies and POI, due to alterations in the transcription factor (TF) FOXL2. Over the years, we have contributed to a better understanding of its molecular function, pathogenic mechanisms, targets and partners. We use FOXL2 as a model to explore the basis of the specific recognition of a target by a TF and the influence of partners and post-translational modifications in this process. We are also investigating the involvement of FOXL2 in adult granulosa cell tumors (AGCT). Indeed, a recurrent somatic mutation in FOXL2, leading to the p.C134W substitution has been detected in more than 97% of AGCTs, suggesting that this mutation is a key element (driver) in their formation. We are actively studying the pathogenic mechanisms of this mutation using CRISPR-Cas9 modified cell lines, an animal model and genomic tools. For the juvenile form of GCTs, we have recently reported the presence of insertions in the AKT1 oncogene that are likely responsible for the tumors, paving the way for further research. Finally, we are taking advantage of the power of current genomic technology to perform exome sequencing in familial and isolated cases of POI to uncover genes whose mutations are responsible for this condition. We have thus shown the involvement in POI of genes such as STAG3 or more recently MEIOB.
Keywords: Ovary, transcription factor, gene regulation, omics analysis, IOP, cancer
+33 (0)157278116 reiner.veitia(at)ijm.fr
The main objective of the research carried out by our team is the study of ovarian function through molecular genetics. A historical subject of the group has been the analysis of the Blepharophimosis syndrome (craniofacial anomalies and premature ovarian insufficiency or POI), due to alterations in the transcription factor FOXL2. Over the years, we have contributed to a better understanding of the molecular function of FOXL2, its mechanisms of pathogenicity and the discovery of numerous targets and partners. FOXL2 provides an excellent model to study the combinatorial regulation of transcription, as it modulates a series of apparently unrelated processes (e.g. cholesterol and steroid metabolism, apoptosis, cell cycle, free radical detoxification, etc.). Thus, we use FOXL2 as a model to explore the basis of specific target recognition by a transcription factor and the influence of its partners and post-translational modifications on this process. To do so, we use state-of-the-art genomics and proteomics tools.
Caption: FOXL2 interactome: protein-protein interaction network for 255 FOXL2 partners identified by co-immunoprecipitation and mass spectrometry.
FOXL2 has also opened an avenue of research into ovarian granulosa cell tumors (GCTs), which account for up to 8% of all ovarian cancers. Two distinct subtypes of GCTs have been described: juvenile and adult forms. The adult type occurs most often during perimenopause and is characterized by late recurrence (up to 40 years after treatment of the primary tumor). The juvenile form (JGCT) tends to occur in the prepubertal period. A recurrent somatic mutation in FOXL2, leading to the p.C134W substitution has been detected in more than 97% of AGCTs, suggesting that this mutation is a driver of their formation. We are actively investigating the pathogenic mechanisms of this mutation using CRISPR-Cas9 modified cell lines, an animal model and genomic tools.
The molecular basis of JGCT is less well understood. We recently found tandem duplications in the reading frame of the AKT1 oncogene that affect the pleckstrin-homology domain (PHD) of the protein in over 60% of JGCTs. The effects of these mutations are currently being studied in cell and Drosophila models.
Caption: HeLa cells expressing the normal version of AKT1 (right) and one of the mutated versions found in ovarian tumors (left) (core: blue, AKT1: red).
Finally, we are taking advantage of the power of current genomic technology to discover new genes involved in female infertility due to POI, by performing exome sequencing in familial and isolated cases of this disorder. The functions of candidate genes discovered in these analyses are or will be studied using molecular approaches and animal models.
Reply to “An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2”. Veitia RA, Pilsworth J, Todeschini AL, Huntsman D.EMBO J. 2021 Aug 16;40(16):e107517. doi: 10.15252/embj.2020107517.PMID: 34396573
FOXL2 in adult-type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene? Pilsworth JA, Todeschini AL, Neilson SJ, Cochrane DR, Lai D, Anttonen M, Heikinheimo M, Huntsman DG, Veitia RA.J Pathol. 2021 Nov;255(3):225-231. doi: 10.1002/path.5771. Epub 2021 Sep 1.PMID: 34338304
Insights into the pathogenicity of missense variants in the forkhead domain of FOX proteins underlying Mendelian disorders. Bermúdez-Guzmán L, Veitia RA. Hum Genet. 2021 Jul;140(7):999-1010.
Forkhead Transcription Factors in Health and Disease. Herman L, Todeschini AL, Veitia RA.Trends Genet. 2021 May;37(5):460-475 (Review).
Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion. Herman L, Legois B, Todeschini AL, Veitia RA.FASEB J. 2021 Apr;35(4):e21355. doi: 10.1096/fj.202002444R.PMID: 33749886
A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1. Felipe-Medina N, Caburet S, Sánchez-Sáez F, Condezo YB, de Rooij DG, Gómez-H L, Garcia-Valiente R, Todeschini AL, Duque P, Sánchez-Martin MA, Shalev SA, Llano E, Veitia RA, Pendás AM.Elife. 2020 Aug 26;9:e56996. doi: 10.7554/eLife.56996.PMID: 32845237 Free
An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes. Alvarez-Mora MI, Todeschini AL, Caburet S, Perets LP, Mila M, Younis JS, Shalev S, Veitia RA.Clin Genet. 2020 Sep;98(3):293-298. doi: 10.1111/cge.13803. Epub 2020 Jul 28.PMID: 32613604
DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation. Elzaiat M, Flatters D, Sierra-Díaz DC, Legois B, Laissue P, Veitia RA.Hum Genet. 2020 Nov;139(11):1455-1470.
Conventional and unconventional interactions of the transcription factor FOXL2 uncovered by a proteome-wide analysis. Penrad-Mobayed M, Perrin C, Herman L, Todeschini AL, Nigon F, Cosson B, Caburet S, Veitia RA.FASEB J. 2020 Jan;34(1):571-587. doi: 10.1096/fj.201901573R. Epub 2019 Nov 25.PMID: 31914586
A truncating MEIOB mutation responsible for familial primary ovarian insufficiency abolishes its interaction with its partner SPATA22 and their recruitment to DNA double-strand breaks. Caburet S, Todeschini AL, Petrillo C, Martini E, Farran ND, Legois B, Livera G, Younis JS, Shalev S, Veitia RA.EBioMedicine. 2019 Apr;42:524-531. doi: 10.1016/j.ebiom.2019.03.075. Epub 2019 Apr 15.PMID: 31000419
2016-2020 : Laëtitia Herman, thesis defense: 22/09/2020 « Caractérisation moléculaire du rôle de FOXL2 et de ses partenaires dans l’ovaire sain et pathologique »
2012-2015 : Laurianne Bessière, thesis defense: 16/09/2015 « Exploration génomique et fonctionnelle des tumeurs des cellules de la granulosa ovarienne »
2009-2013 : Adrien Georges, thesis defense: 28/06/2013 « FOXL2 : un déterminant de la signalisation dans l’ovaire »
2007-2011 : Bérénice Benayoun, thesis defense: 28/01/2011 « FOXL2 : un facteur de transcription essentiel de l’ovaire, à l’interface entre la réponse au stress cellulaire et la suppression tumorale »
2006-2009 : Aurélie Dipiétromaria, thesis defense: 28/09/2009 « Etudes des conséquences fonctionnelles des mutations de FOXL2 : gène impliqué dans le syndrome du BPES »
2005-2008 : Franck Batista Pelaez, thesis defense: 13/06/2008 « Les cibles transcriptionnelles de FOXL2, un facteur de transcription impliqué dans le développement et le maintien de la fonction ovarienne »
2005-2008 : Lara Moumné, thesis defense: 14/05/2008 « Etude fonctionnelle des mutations affectant FOXL2 : un acteur clé du développement de l’ovaire chez les vertébrés »
2002-2006 : Julie Cocquet thesis defense: 2006 « Evolution, expression et structure de FOXL2, un gène impliqué dans la fertilité féminine »
Studies on adult ovarian granulosa cell tumours (AGCTs) and the FOXL2 transcription factor: Team of E. de Baere, Ghent Belgium. Team of N. Binart, Kremlin-Bicêtre, France. F. Poulat, Montpellier, France. Team of M. Anttonen, Helsinki, Finland. Team D. Huntsman, Vancouver, Canada. Team of Alberto Pendas, Salamanca, Spain.
Studies on juvenile ovarian granulosa cell tumours (JGCTs) and the AKT1 oncoprotein: S. Sarnacki and L. Galmiche, Paris. N. Kalfa and C. Sultan, Montpellier. J. Prat and E. d’Angelo, Barcelona, Spain. Malcolm Donaldson, Glasgow, United Kingdom.
Studies on genes involved in premature ovarian failure: Maria Isabel Alvarez-Mora and Montserrat Mila, Barcelona, Spain. Gabriel Livera’s team, Fontenay aux Roses, France. Johnny S. Younis, Safed, Israel. Team of Stavit Shalev, Afula, Israel. Alberto Pendas’ team, Salamanca, Spain.
Translated with www.DeepL.com/Translator (free version)
1) ANR (National Agency for Research) : OVARYPROTECT : Interaction entre la signalisation PKA et TRIM28 dans la maintenance et la pathologie ovarienne
2) GEFLUC (Groupement des Entreprises Françaises dans la Lutte contre le Cancer): Ovarian cancer: FOXL2-C134W impact on cell-cell or cell-ECM adhesion.