Our research activities focus on the study of the mechanisms that control gene expression and morphogenesis. As a paradigm, we study the function played by two transcription factors (HNF1alpha and beta, encoded by HNF1A and HNF1B genes). These genes are frequently mutated in patients that suffer from diabetes and/or renal developmental dysfunctions.
Cell growth, differentiation and morphogenesis are key events whose perturbation may lead to severe developmental pathologies. These processes are largely controlled by complex transcriptional circuitries where transcription factors play a crucial role. In this context, the analysis of the function of transcription factors and the mechanism of their action offers a unique perspective for understanding complex biological processes and physiopathology. In the last years, as a paradigm, we have chosen to study the function of HNF1alpha and beta, a small family of transcription factors, whose mutations are frequently found in patients that suffer from a complex set of dysfunctions including defective renal development, renal disease and insulin secretion defects.
Morphogenesis of kidney
We have shown the HNF1beta plays a crucial role in both nephron morphogenesis during embryogenesis as well as in maintenance of renal tissue differentiation in postnatal life. Our objective is to characterize the genetic program played by HNF1B to understand the mechanisms of the dysfunctions linked to its deficiency.
The control of gene expression
We demonstrated that HNF1alpha and beta are bookmarking transcription factors. In fact, they are able to remain bound to mitotic chromatin during cell division. This characteristic seems to play an important role for the postmitotic gene reactivation of specific target genes. Our objective is to characterize the molecular mechanisms linked to their bookmarking activity.
The mechanisms of the variability of the phenotype linked to HNF1A and HNF1B deficiency
The penetrance and expressivity of the phenotype of HNF1alpha and beta patients is extremely variable suggesting the existence of modifier genes. In this respect, with the use of a mouse model for HNF1A deficiency we identified a powerful genetic suppressor locus of the diabetes mellitus linked to the deficiency of HNF1alpha. Our objective is to identify and characterize the gene variants and the signalling networks linked to the suppression. In parallel, we are currently trying to identify genes whose perturbation may impact on the potency of HNF1A and HNF1B
Miao Z, Balzer MS, Ma Z, Liu H, Wu J, Shrestha R, Aranyi T, Kwan A, Kondo A, Pontoglio M, Kim J, Li M, Kaestner KH, Susztak K. Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat Commun. 2021 Apr 15;12(1):2277. doi: 10.1038/s41467-021-22266-1. PMID: 33859189; PMCID: PMC8050063.
Blanc T, Goudin N, Zaidan M, Traore MG, Bienaime F, Turinsky L, Garbay S, Nguyen C, Burtin M, Friedlander G, Terzi F, Pontoglio M. Three-dimensional architecture of nephrons in the normal and cystic kidney. Kidney Int. 2021 Mar;99(3):632-645. doi: 10.1016/j.kint.2020.09.032. Epub 2020 Oct 31. PMID: 33137337.
Fiorentino A, Christophorou A, Massa F, Garbay S, Chiral M, Ramsing M, Rasmussen M, Gubler MC, Bessieres B, Heidet L, Fischer E, Pontoglio M. Developmental Renal Glomerular Defects at the Origin of Glomerulocystic Disease. Cell Rep. 2020 Oct 27;33(4):108304. doi: 10.1016/j.celrep.2020.108304. PMID: 33113370.
Miceli C, Roccio F, Penalva-Mousset L, Burtin M, Leroy C, Nemazanyy I, Kuperwasser N, Pontoglio M, Friedlander G, Morel E, Terzi F, Codogno P, Dupont N. The primary cilium and lipophagy translate mechanical forces to direct metabolic adaptation of kidney epithelial cells. Nat Cell Biol. 2020 Sep;22(9):1091-1102. doi: 10.1038/s41556-020-0566-0. Epub 2020 Aug 31. PMID: 32868900.
Villemain L, Prigent S, Abou-Lovergne A, Pelletier L, Chiral M, Pontoglio M, Foufelle F, Caruso S, Pineau R, Rebouissou S, Chevet E, Zucman-Rossi J, Combettes L. Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α. Cancers (Basel). 2020 Aug 7;12(8):2213. doi: 10.3390/cancers12082213. PMID: 32784704; PMCID: PMC7464972.
Bonucci M, Kuperwasser N, Barbe S, Koka V, de Villeneuve D, Zhang C, Srivastava N, Jia X, Stokes MP, Bienaimé F, Verkarre V, Lopez JB, Jaulin F, Pontoglio M, Terzi F, Delaval B, Piel M, Pende M. mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division. Nat Commun. 2020 Jun 24;11(1):3200. doi: 10.1038/s41467-020-16978-z. PMID: 32581239; PMCID: PMC7314806.
Zaidan M, Burtin M, Zhang JD, Blanc T, Barre P, Garbay S, Nguyen C, Vasseur F, Yammine L, Germano S, Badi L, Gubler MC, Gallazzini M, Friedlander G, Pontoglio M, Terzi F. Signaling pathways predisposing to chronic kidney disease progression. JCI Insight. 2020 May 7;5(9):e126183. doi: 10.1172/jci.insight.126183. PMID: 32376805; PMCID: PMC7253021.
Chan SC, Zhang Y, Pontoglio M, Igarashi P. Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor. Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24133-24142. doi: 10.1073/pnas.1909452116. Epub 2019 Nov 11. PMID: 31712448; PMCID: PMC6883834.
Ducat A, Vargas A, Doridot L, Bagattin A, Lerner J, Vilotte JL, Buffat C, Pontoglio M, Miralles F, Vaiman D. Low-dose aspirin protective effects are correlated with deregulation of HNF factor expression in the preeclamptic placentas from mice and humans. Cell Death Discov. 2019 May 10;5:94. doi: 10.1038/s41420-019-0170-x. PMID: 31098302; PMCID: PMC6510804.
Chan SC, Zhang Y, Shao A, Avdulov S, Herrera J, Aboudehen K, Pontoglio M, Igarashi P. Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease. J Am Soc Nephrol. 2018 Oct;29(10):2493-2509. doi: 10.1681/ASN.2018040437. Epub 2018 Aug 10. PMID: 30097458; PMCID: PMC6171276.
Billot K, Coquil C, Villiers B, Josselin-Foll B, Desban N, Delehouzé C, Oumata N, Le Meur Y, Boletta A, Weimbs T, Grosch M, Witzgall R, Saunier S, Fischer E, Pontoglio M, Fautrel A, Mrug M, Wallace D, Tran PV, Trudel M, Bukanov N, Ibraghimov-Beskrovnaya O, Meijer L. Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8. Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F57-F73. doi: 10.1152/ajprenal.00489.2017. Epub 2018 Mar 14. PMID: 29537311; PMCID: PMC6087785.
Phelep A, Laouari D, Bharti K, Burtin M, Tammaccaro S, Garbay S, Nguyen C, Vasseur F, Blanc T, Berissi S, Langa-Vives F, Fischer E, Druilhe A, Arnheiter H, Friedlander G, Pontoglio M, Terzi F. MITF - A controls branching morphogenesis and nephron endowment. PLoS Genet. 2017 Dec 14;13(12):e1007093. doi: 10.1371/journal.pgen.1007093. PMID: 29240767; PMCID: PMC5746285.
Casemayou A, Fournel A, Bagattin A, Schanstra J, Belliere J, Decramer S, Marsal D, Gillet M, Chassaing N, Huart A, Pontoglio M, Knauf C, Bascands JL, Chauveau D, Faguer S. Hepatocyte Nuclear Factor-1β Controls Mitochondrial Respiration in Renal Tubular Cells. J Am Soc Nephrol. 2017 Nov;28(11):3205-3217. doi: 10.1681/ASN.2016050508. Epub 2017 Jul 24. PMID: 28739648; PMCID: PMC5661272.
Aboudehen K, Noureddine L, Cobo-Stark P, Avdulov S, Farahani S, Gearhart MD, Bichet DG, Pontoglio M, Patel V, Igarashi P. Hepatocyte Nuclear Factor-1β Regulates Urinary Concentration and Response to Hypertonicity. J Am Soc Nephrol. 2017 Oct;28(10):2887-2900. doi: 10.1681/ASN.2016101095. Epub 2017 May 15. PMID: 28507058; PMCID: PMC5619957.
Patitucci C, Couchy G, Bagattin A, Cañeque T, de Reyniès A, Scoazec JY, Rodriguez R, Pontoglio M, Zucman-Rossi J, Pende M, Panasyuk G. Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription. J Clin Invest. 2017 May 1;127(5):1873-1888. doi: 10.1172/JCI90327. Epub 2017 Apr 10. PMID: 28394260; PMCID: PMC5409083.
Garcia-Gonzalez MA, Carette C, Bagattin A, Chiral M, Makinistoglu MP, Garbay S, Prévost G, Madaras C, Hérault Y, Leibovici M, Pontoglio M. A suppressor locus for MODY3-diabetes. Sci Rep. 2016 Oct 21;6:35697. doi: 10.1038/srep35697. Erratum for: Sci Rep. 2016 Sep 26;6:33087. PMID: 27767025; PMCID: PMC5073365.
Lerner J, Bagattin A, Verdeguer F, Makinistoglu MP, Garbay S, Felix T, Heidet L, Pontoglio M. Human mutations affect the epigenetic/bookmarking function of HNF1B. Nucleic Acids Res. 2016 Sep 30;44(17):8097-111. doi: 10.1093/nar/gkw467. Epub 2016 May 26. PMID: 27229139; PMCID: PMC5041451.
Bienaimé F, Muorah M, Yammine L, Burtin M, Nguyen C, Baron W, Garbay S, Viau A, Broueilh M, Blanc T, Peters D, Poli V, Anglicheau D, Friedlander G, Pontoglio M, Gallazzini M, Terzi F. Stat3 Controls Tubulointerstitial Communication during CKD. J Am Soc Nephrol. 2016 Dec;27(12):3690-3705. doi: 10.1681/ASN.2015091014. Epub 2016 May 6. PMID: 27153926; PMCID: PMC5118479.
Terryn S, Tanaka K, Lengelé JP, Olinger E, Dubois-Laforgue D, Garbay S, Kozyraki R, Van Der Smissen P, Christensen EI, Courtoy PJ, Bellanné-Chantelot C, Timsit J, Pontoglio M, Devuyst O. Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule. Kidney Int. 2016 May;89(5):1075-1089. doi: 10.1016/j.kint.2016.01.027. Epub 2016 Mar 29. PMID: 27083284.
Aboudehen K, Kim MS, Mitsche M, Garland K, Anderson N, Noureddine L, Pontoglio M, Patel V, Xie Y, DeBose-Boyd R, Igarashi P. Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism. J Am Soc Nephrol. 2016 Aug;27(8):2408-21. doi: 10.1681/ASN.2015060607. Epub 2015 Dec 28. PMID: 26712526; PMCID: PMC4978044.
Hajarnis SS, Patel V, Aboudehen K, Attanasio M, Cobo-Stark P, Pontoglio M, Igarashi P. Transcription Factor Hepatocyte Nuclear Factor-1β (HNF-1β) Regulates MicroRNA-200 Expression through a Long Noncoding RNA. J Biol Chem. 2015 Oct 9;290(41):24793-805. doi: 10.1074/jbc.M115.670646. Epub 2015 Aug 19. PMID: 26292219; PMCID: PMC4598991.
Canaud G, Bienaimé F, Viau A, Treins C, Baron W, Nguyen C, Burtin M, Berissi S, Giannakakis K, Muda AO, Zschiedrich S, Huber TB, Friedlander G, Legendre C, Pontoglio M, Pende M, Terzi F. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med. 2013 Oct;19(10):1288-96. doi: 10.1038/nm.3313. Epub 2013 Sep 22. PMID: 24056770.
Patel V, Williams D, Hajarnis S, Hunter R, Pontoglio M, Somlo S, Igarashi P. miR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10765-70. doi: 10.1073/pnas.1301693110. Epub 2013 Jun 12. PMID: 23759744; PMCID: PMC3696812.
Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler MC, Heidet L, Pontoglio M, Fischer E. Hepatocyte nuclear factor 1β controls nephron tubular development. Development. 2013 Feb;140(4):886-96. doi: 10.1242/dev.086546. PMID: 23362349.
Laouari D, Burtin M, Phelep A, Bienaime F, Noel LH, Lee DC, Legendre C, Friedlander G, Pontoglio M, Terzi F. A transcriptional network underlies susceptibility to kidney disease progression. EMBO Mol Med. 2012 Aug;4(8):825-39. doi: 10.1002/emmm.201101127. Epub 2012 Jun 18. PMID: 22711280; PMCID: PMC3494079.
Roelandt P, Antoniou A, Libbrecht L, Van Steenbergen W, Laleman W, Verslype C, Van der Merwe S, Nevens F, De Vos R, Fischer E, Pontoglio M, Lemaigre F, Cassiman D. HNF1B deficiency causes ciliary defects in human cholangiocytes. Hepatology. 2012 Sep;56(3):1178-81. doi: 10.1002/hep.25876. Epub 2012 Jul 19. PMID: 22706971.
Panasyuk G, Espeillac C, Chauvin C, Pradelli LA, Horie Y, Suzuki A, Annicotte JS, Fajas L, Foretz M, Verdeguer F, Pontoglio M, Ferré P, Scoazec JY, Birnbaum MJ, Ricci JE, Pende M. PPARγ contributes to PKM2 and HK2 expression in fatty liver. Nat Commun. 2012 Feb 14;3:672. doi: 10.1038/ncomms1667. PMID: 22334075; PMCID: PMC3293420.
Marco Pontoglio graduated in Milan University, Italy and then moved to Pasteur Institute in France to do a postdoctoral training with Prof Moshe Yaniv in 1991. His field of research was the control of gene expression and the characterization of the first tissue specific transcription factors. In 1997 he started his career as a researcher (permanent position) in CNRS and in 2002 he became Team Leader. In 2008 he moved his group to Cochin Institute in Paris and eventually joined the INEM Institute on the Necker Campus in 2019.
The scientific activity of his group is centered on the study the roles played by the transcription factors HNF1alpha and beta in the control of gene expression and in the control of morphogenesis during development. During the last years, the studies of his group have shown that HNF1beta control the expression of several renal cystic genes whose mutation is responsible for polycystic kidney disease. His results have indicated that renal tubular cells have an intrinsic planar cell polarization that accounts for the peculiar alignment of their mitotic spindles with the tubular axis during nephron elongation. Loss of oriented cell division accompanies the dilation of tubular structures in several PKD rodent models. More recently the team has uncovered a peculiar aspect of the control of gene expression: they demonstrated that HNF1beta is a bookmarking factor that is involved in gene expression reprogramming after the phase of mitotic gene silencing.