Le projet DEVO-DECODE est porté par l’Institut Imagine
CONTEXT & OBJECTIVES
Despite important advances in genomics, 45% of the genetic diseases remain with an unknown cause, urging the need to increase our scientific and clinical knowledge of these diseases to provide the patients and their families with long-awaited diagnostic and therapeutic solutions. Among these pathologies, the developmental disorders represent a heterogeneous, multifactorial group, affecting one or several organs or tissues, as in the brain anomalies, head and neck malformations, heart defects, skeletal disorders, and eye and auditory diseases. They are present in about 2 to 3% of live births – affecting approximately 150,000 newborns each year in Europe, associated with high-rate mortality, thus representing a major social, economic and health issue. The Devo- Decode project proposes to carry out in-depth investigations beyond the coding regions of the genome, representing 1.3% of the whole DNA only. By focusing on the non-coding regions of the genome (i.e. , representing 98.7% of the entire DNA), the objective is to find new relevant variants explaining the pathophysiological impairments. Led by Prof Stanislas Lyonnet, the Devo-Decode project will build on the unique organisation of the Imagine Institute, gathering in the same place patients, medical doctors, researchers, and engineers. 8 reference centres and clinical units for rare diseases, 8 research laboratories and 8 core facilities, working in close interaction, will participate in the project.
“Le soutien de MSDAVENIR permettra une meilleure connaissance du phénotype et de l’histoire de ces maladies génétiques, grâce à une combinaison d’études génomiques et physiopathologiques, soulignant la nécessité d’une approche translationnelle réunissant au sein d’un même site des équipes de référence, multidisciplinaires, de recherche et cliniques, toutes expertes dans leurs domaines.”
Pr Stanislas LYONNET
Directeur de l’Institut Imagine, Coordinateur du projet DEVO-DECODE
Results from the team of Heart Morphogenesis led by Sigolène Meilhac
How a specific shape determines organ function is a central question in Developmental Biology. My team uses the mammalian heart as a striking model of morphogenesis, in which the alignment of cardiac chambers is essential for the function of orchestrating double blood circulation.
Unmet medical needs in human cardiology include understanding the origins of the most frequent congenital malformation for which poor genetic counselling is available. Advances in heart morphogenesis have been hampered by an absence of tools and methods able to deliver accurate, quantitative descriptions of cardiac anomalies taking into the spatio-temporal context of development at sufficient resolution and able to disentangle the specific contributions of different factors. We aim to uncover embryological mechanisms at different scales (molecular, cellular, anatomical) generating the 3D shape of the heart and to assess the impact on human diseases.
The secreted factor Nodal has been shown to be a major left determinant. Although it is associated with severe congenital heart defects, how Nodal is sensed by organ-specific precursor cells to generate asymmetric organogenesis is currently unknown. In the publication Desgrange et al. Developmental Cell 2020, we report that Nodal is transiently active in precursors of the mouse heart tube poles, before the morphological changes of heart looping. In conditional mutants, we show that Nodal is not required to initiate asymmetric morphogenesis. We provide evidence of a heart-specific random generator of asymmetry that is independent of Nodal. Using 3D quantifications and simulations, we demonstrate that Nodal functions as a bias of this mechanism: it is required to amplify and coordinate opposed left-right asymmetries at the heart tube poles, thus generating a robust helical shape. We identify downstream effectors of Nodal signalling by RNA siquencing, regulating asymmetries in cell proliferation, cell differentiation and extra- cellular matrix composition. Our work provides novel insight into how Nodal regulates asymmetric organogenesis.
Nodal conditional mutants provide a model of non-penetrant anomalies in heart looping. In the future, we will use our multi-modality imaging pipeline (Desgrange et al., Disease Models and Mechanisms 2019) to correlate looping anomalies with specific congenital heart defects. Thus, our work provides novel insight into the mechanism of complex congenital heart defects with impaired blood circulation.
Results from the team of Genetics in Ophthalmology led by Jean-Michel Rozet
Congenital microcoria (MCOR) is a rare autosomal dominant disease characterized by unreactive pinhole pupils lacking iris dilator muscle (DM). Open-angle glaucoma (GLC) and high myopia (HM) are frequent in MCOR. In 2015, we ascribed the disease to 13q32.1 deletions. By studying mouse models, we generated, we suggest that MCOR is due to unanticipated complex mechanisms linked with 3D regulation of gene expression. We show aberrant expression of the SOX21 transcription factor in the iris, the binding of which to a regulatory region of TGFb-2 induces overexpression and accumulation of its product in the iris and aqueous humor. Consistent with the known link between TGFb-2 accumulation in the aqueous humor and open-angle GLC, our results indicate optic nerve degradation that is the hallmark of GLC, including Primary open-angle glaucoma (POAG).
Furthermore, we show that SOX21 is expressed in the posterior but not anterior pigment epithelium of the iris which gives rise to the dilator muscle, suggesting a TGFb-2 paracrine signalling. Together our data suggest that overexpression of TGFb-2 links the iris malformation, GLC and even myopia (TGFb-2 contributes to axial elongation of the eye) in MCOR, making this rare disease a highly valuable model to analyse eye development, the mechanisms of common POAG and to develop treatments.
To verify our hypothesis, we will combine analysis of mouse models at different developmental stages with studies in human iris cell models and patients affected with MCOR and POAG, respectively. We use sophisticated tools including genome editing, a higher-resolution study of the 3D architecture of the genome and single-cell RNA-sequencing available to elucidate the mechanisms of MCOR and associated symptoms and to provide an atlas of iris and CB cell populations. We will take advantage of our unique cohort ofmultigenerational MCOR families with and without associated symptoms, to identify genetic factors that predispose to GLC in MCOR and assess them in a POAG cohort.
Methods and pharmaceutical compositions for treating ocular diseases. (Brevet SOX21 – ep 20 305 396).
1. Transient Nodal Signaling in Left Precursors Coordinates Opposed Asymmetries Shaping the Heart Loop. Desgrange et al. Dev Cell 2020 Nov 23;55(4):413-431.e6.
2. Congenital Microcoria: Clinical Features and Molecular Genetics. Angée C et al. Genes (Basel). 2021 Apr 22;12(5):624. doi: 10.3390/genes12050624.
3. Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits. Fregeac J et al. Mol Autism. 2020 Mar 30;11(1):22.
4.MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia. Ucuncu E, et al. Nat Commun. 2020 Nov 30;11(1):6087.
5. cGAS-mediated induction of type I interferon due to inborn errors of histone pre- mRNA processing. Uggenti C et al. Nature Genetics 2020;52:1364-1372.
6. Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Rice GI et al. Human Mutation 2020;41:837-849
7. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies. Lodi L et al. Journal of Clinical Immunology 2021;41:603-609.
8. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signalling. Lepelley A et al. Journal of Experimental Medicine 2020;217:e20200600.
9. ADAR1 mediated regulation of neural crest-derived melanocytes and Schwann cell development. Gacem N et al. Nature Communications 2020;11:198.
10. Generation of an iPSC line (IMAGINi022-A) from a patient carrying a SOX10 missense mutation and presenting with deafness, depigmentation and progressive neurological impairment. Banal C, et al. Stem Cell Research 2020:48:101936.