Control of gene expression (COdEX)

In the context of post-transcriptional control, a combinatorial code between CIS (RNA sequence domains) and TRANS elements (RNA-binding proteins and microRNAs) enables a fine control of the fate of target RNAs, by masking or exposing specific binding sites.
The challenge is now to integrate the interplay between microRNA- and RNA-binding proteins in subcellular compartments to decode the complexity of post-transcriptional control in human cell physiology/pathology. Antisense oligonucleotides and pharmacological antagonists for small noncoding RNA biogenesis are being explored to effect cell-specific changes in gene expression as the basis for ‘RNA therapeutics’.

Selected publications :

1. Serra F*, Bottini S*, Pratella D, Stathopoulou MG, Sebille W, El-Hami L, et al. Trabucchi M# (2021) Systemic CLIP-seq analysis and game theory approach to model microRNA mode of binding. Nucleic Acids Res. 49(11):e66.
2. M. Trabucchi# and R. Mategot (2019) Subcellular heterogeneity of the microRNA machinery. Trends in Genetics 35(1): 15. (Review)
3. S. Bottini, D. Pratella, V. Grandjean, E. Repetto, M. Trabucchi# (2018) Recent development on CLIP-seq analysis and implications in miRNA targeting. Briefings in Bioinformatics doi: 10.1093/bib/bbx063.
4. S. Bottini*, N. Hamouda-Tekaya*, R. Mategot, L.E. Zaragosi, S. Audebert, S. Pisano, V. Grandjean, C. Mauduit, M. Benahmed, P. Barbry, E. Repetto, M. Trabucchi# (2017) Post-transcriptional gene silencing mediated by microRNAs is controlled by nucleoplasmic Sfpq. Nature Communications 8(1):1189.
5. S. Bottini, N. Hamouda-Tekaya, B. Tanasa, L.E. Zaragosi, V. Grandjean, E. Repetto, M. Trabucchi# (2017) From benchmarking HITS-CLIP peak detection programs to a new method for identification of miRNA-binding sites from Ago2-CLIP data. Nucleic Acids Research 45(9):e71.
6. P. Bruscella, S. Bottini, C. Baudesson, J.M, Pawlotsky, C. Feray, M. Trabucchi# (2017) Viruses and miRNAs: More Friends than Foes. Front Microbiol. 8:824. (Review)
7. B. Siddeek, N. Lakhdari, L. Inoubli, R. Paul-Bellon, V. Isnard, E. Thibault, A. Bongain, D. Chevalier, E. Repetto, M. Trabucchi, J.F. Michiels, U. Simeoni, M. Urtizberea, C. Mauduit, M. Benahmed#  (2016) Developmental epigenetic programming of adult germ cell death disease: polycomb protein EZH2 -miR-101 pathway. Epigenomics 8(11):1459-1479.
8. E. Repetto, P. Briata, N. Kuziner, B.D. Harfe, M.T. McManus, R. Gherzi, M.G. Rosenfeld, M. Trabucchi# (2012) Let-7b/c enhance the stability of a tissue-specific mRNA during mammalian organogenesis as part of a feedback loop involving KSRP. Plos Genetics Jul;8(7): e1002823.
9. Q. Hu, B. Tanasa*, M. Trabucchi*, W. Li, J. Zhang, K.A. Ohgi, D.W. Rose, C.K. Glass, M.G. Rosenfeld (2012) DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation. Nature Structural & Molecular Biology 19, 1168-1175.
10. R. Gherzi*, M. Trabucchi*, M. Ponassi, I.E. Gallouzi, M.G. Rosenfeld, P. Briata (2010). Pitx2, a required factor in myoblast differentiation, is phosphorylated by AKT and controls cyclin D1 mRNA decay. Cell Death & Differ.
11. M. Trabucchi, P. Briata, M.F. Garcia-Mayoral, A.D. Haase, W. Filipowicz, A. Ramos, R. Gherzi, M.G. Rosenfeld (2009). The RNA-binding Protein KSRP Promotes the Biogenesis of a Subset of miRNAs. Nature 459:1010-1014.

The deregulation of the phenotype and function of macrophages is increasingly being recognized in several inflammatory and autoimmune disorders. We and others demonstrated that different classes of small noncoding RNAs, such as YRNAs, play a role in gene expression (de)regulation in macrophage functions in health and disease. We are investigating the mechanisms and functional consequences of Ro60-YRNA complex deregulation in autoimmune diseases and their cardiometabolic comorbidities. From a clinical point of view, the data generated here will serve to mechanistically evaluate the resistance of immune-suppressor treatments to systemic immune and inflammatory diseases.

Publications sélectionnées :

1. Costa VL, Ruidavets JB, Bongard V, Perret B, Repetto E, Stathopoulou MG, Serra F, Benahmed M, Mauduit C, Grandjean V, Ferrières J, Martinez LO#, Trabucchi M.# (2021) Prediction of coronary heart disease incidence in a general male population by circulating non-coding small RNA sRNY1-5p in a nested case-control study. Sci Rep. 11(1):1837. doi: 10.1038/s41598-021-81221-8.
2. Martis N, Jamme M, Bagnis-Isnard C, Pouteil-Noble C, Presne C, Vigneau C, et al. (2021) Systemic autoimmune disorders associated with thrombotic microangiopathy: A cross-sectional analysis from the French National TMA registry: Systemic autoimmune disease-associated TMA. Eur J Intern Med.
3. Levraut M, Legros L, Drappier C, Béné MC, Queyrel V, Raynaud S, Martis N (2020) Low prevalence of JAK2 V617F mutation in patients with thrombosis and normal blood counts: a retrospective impact study. J Thromb Thrombolys. 50(4):995-1003.
4. Z. Hizir, S. Bottini, V. Grandjean, M. Trabucchi#, E. Repetto# (2017) RNY-derived small RNAs promotes macrophage inflammation and cell death. Cell Death & Disease 8:e2530.
5. Z. Hizir, M. Trabucchi#, E. Repetto# (2016) Valeur diagnostique des petits ARN dérivés des Y-RNAs dans les cardiopathies coronariennes. Med Sci (Paris). 32(3):248-51. (Review)
6. E. Repetto#, L. Lichtenstein, Z. Hizir, N. Tekaya, M. Benahmed, J.B. Ruidavets, L.E. Zaragosi, B. Perret, L. Bouchareychas, A. Genoux, R. Lotte, R. Ruimy, J. Ferrières, P. Barbry, L.O. Martinez, M. Trabucchi#. (2015) RNY-derived small RNAs as a signature of Coronary Artery Disease. BMC Medicine 13(1):259.
7. S. Saccani# and M. Trabucchi# (2015) Regulation of stimulus-inducible gene expression in myeloid cells. Seminars in Immunology Feb;27(1):33-43 (Review)
8. T. Ruggiero*, M. Trabucchi*, F. De Santa, S. Zupo, B.D. Harfe, M.T. McManus, M.G. Rosenfeld, P. Briata, R. Gherzi (2009). LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J23:2898-2908.

Although the molecular mechanism(s) involved in such a process remains unclear, we have evidenced the central role of small non-coding RNAs in sperm as vector of inheritance. We have developed mouse models for paternal epigenetic inheritance of cardiometabolic pathologies by exposing male progenies to unhealthy diets for multiple generations. Generation after generation, the susceptibility to develop features of cardiometabolic disorders increased in the offspring, as well as the severity of the pathologies. The role of deregulated small non-coding RNAs in sperm in the establishment of new epigenetic profiles is investigated. Research in human samples is also conducted to associate the deregulation of sperm small non-coding RNAs to the development of cardiometabolic disorders.

Selected publications:

1. Gong P, Bailbé D, Bianchi L, Pommier G, Liu J, Tolu S, Stathopoulou MG, Portha B, Grandjean V, Movassat J. Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner (2021). Biomolecules. 2021 May 18;11(5):751.
2. Raad G, Serra F, Martin L, Derieppe MA, Gilleron J, Costa VL, Pisani DF, Amri EZ, Trabucchi M, Grandjean V# (2021). Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice. Elife. Mar 30;10:e61736. 
3. Raad G, J Azouri, K Rizk, N Zeidan, J Azouri, V Grandjean, M Hazzouri (2019) Adverse Effects of paternal obesity on the motile spermatozoa quality. Plos One. 14(2): e0211837.
4. Raad G, Hazzouri M, Bottini S, Trabucchi M, Azoury J, Grandjean V. (2017) Paternal obesity: how bad is it for sperm quality and progeny health? Clin Androl. Oct 26;27:20.
5. Grandjean V#, S Fourré, DA Fernandes De Abreu, MA Derieppe, JJ Remy and M Rassoulzadegan (2015) RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep 5:18193.
6. Grandjean V, Gounon P, Wagner N, Martin L, Wagner KD, Bernex F, Cuzin F, Rassoulzadegan M. (2009) The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development.  Nov;136(21):3647-55.
7. Kiani J*, V Grandjean*, R Liebers, F Tuorto, H Ghanbarian, F Lyko, F Cuzin, M Rassoulzadegan (2013) RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet. May; 9(5):e1003498.
8. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. (2006) RNA-mediated non-Mendelian inheritance of an inheritance of an epigenetic change in the mouse Nature 431, 469-474.