Previous projects included identifying the needs of the HD community in the field of systems modelling, defining guidelines for developing such approaches (i.e. recommendations on methods best suited for comprehensive analysis of genomic datasets or definition of complex signalling systems) and testing key methods. This is reported in the on-line summaries of the annual meetings of our Working Group and this is illustrated in some of the publications of the Working Group members.

The aims of on-going projects are to develop deeper levels of network-based data integration (current and future datasets) in order to generate increasingly-precise models of the HD process, to associate highly-prioritized targets with the biology of HD and to foster the development of personalized medicine for HD subjects through detection of molecular/genetic signatures that could predict the age-at-onset or progression of HD.

We are aiming to make new algorithms available to the community — covering a large array of applications such as for example analysis/integration of small-RNA-seq data, mRNA-seq data, ChIP-seq data, genetic data, proteomic data and functional data —, to disseminate knowledge on how to use these methods and to discuss new needs/applications.

EHDN Working Groups and members are highly welcome to contact us for help with analysis of existing datasets or help with the design of new projects about the regulation of the HD process and the development of molecular diagnosis/prognosis.

L. Mégret, B. Gris, SS Nair, J. Cevost, M. Wertz, J. Aaronson, J. Rosinski, T. F. Vogt, H. Wilkinson, M. Heiman, C. Néri. 2021. Shape-deformation analysis reveals the temporal dynamics of cell type-specific homeostatic and pathogenic responses to mutant huntingtin. eLife 2021.

R. Alcalá-Vida, J. Seguin, C. Lotz, AM. Molitor, I. Irastorza-Azcarate, A. Awada, N. Karasu, A. Bombardier, B. Cosquer, JL Gomez Skarmeta, JC Cassel, AL Boutillier, T. Sexton, K. Merienne. 2021. Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice. Nature Commun 12, 364 (2021). https://doi.org/10.1038/s41467-020-20605-2

Lee H, Fenster RJ, Pineda SS, Gibbs WS, Mohammadi S, Davila-Velderrain J, Garcia FJ, Therrien M, Novis HS, Gao F et al. 2020. Cell type-Specific transcriptomics reveals that mutant huntingtin leads to mitochondrial RNA release and neuronal innate immune activation. Neuron doi:10.1016/j.neuron.2020.06.021.

Wertz MH, Mitchem MR, Pineda SS, Hachigian LJ, Lee H, Lau V, Powers A, Kulicke R, Madan GK, Colic M et al. 2020. Genome-wide in vivo CNS screening identifies genes that modify CNS neuronal survival and mHTT toxicity. Neuron doi:10.1016/j.neuron.2020.01.004.

Megret L, Nair SS, Dancourt J, Aaronson J, Rosinski J, Neri C. 2020. Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice. BMC Bioinformatics 21: 75. doi: 10.1186/s12859-020-3418-9.

Bigan E, Sasidharan Nair S, Lejeune FX, Fragnaud H, Parmentier F, Megret L, Verny M, Aaronson J, Rosinski J, Neri C. 2019. Genetic cooperativity in multi-layer networks implicates cell survival and senescence in the striatum of Huntington’s disease mice synchronous to symptoms. Bioinformatics doi:10.1093/bioinformatics/btz514.

Merienne N, Meunier C, Schneider A, Seguin J, Nair SS, Rocher AB, Le Gras S, Keime C, Faull R, Pellerin L, Chatton JY, Neri C, Merienne K, Déglon N. 2019. Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures. Cell reports 26: 2477-2493. doi: 10.1016/j.celrep.2019.02.003

Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, Peluso I, Gallego-Flores T, Malik NT, Erikson K, Bleiberg BA et al. 2018. High-throughput functional analysis distinguishes pathogenic, nonpathogenic, and compensatory transcriptional changes in neurodegeneration. Cell Syst 7: 28-40 e24.

Anastasios Mastrokolias, Yavuz Ariyurek, Jelle J Goeman, Erik van Duijn, Raymund AC Roos, Roos C van der Mast, GertJan B van Ommen, Johan T den Dunnen, Peter AC ‘t Hoen, Willeke MC van Roon-Mom. 2015. Huntington’s disease biomarker progression profile identified by transcriptome sequencing in peripheral blood. European Journal of Human Genetics 23 :1349–1356 doi:10.1038/ejhg.2014.281.

Langfelder P, Gao F, Wang N, Howland D, Kwak S, Vogt TF, Aaronson JS, Rosinski J, Coppola G, Horvath S, Yang XW. MicroRNA signatures of endogenous Huntingtin CAG repeat expansion in mice. PLoS One. 2018 Jan 11;13(1):e0190550. doi: 10.1371/journal.pone.0190550. eCollection 2018.

Farina F, Lambert E, Commeau C, Lejeune FX, Roudier N, Fonte C, Parker JA, Boddaert J, Verny M, Baulieu EE and Neri C. The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease. Scientific Reports 2017, 7:4014. doi: 10.1038/s41598-017-04256-w.

Langfelder, P., Cantle, J.P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.H., Ramos, E.M., El-Zein, K., Zhao, Y., et al. (2016). Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice. Nat Neurosci 19, 623-633.

Achour, M., Le Gras, S., Keime, C., Parmentier, F., Lejeune, F.X., Boutillier, A.L., Neri, C., Davidson, I., and Merienne, K. (2015). Neuronal Identity Genes Regulated by Super-Enhancers Are Preferentially Down-Regulated in the Striatum of Huntington’s Disease Mice. Hum Mol Genet 2015. 24:3481-96. doi: 10.1093/hmg/ddv099.

Ring KL, An MC, Zhang N, O’Brien RN, Ramos EM, Gao F, Atwood R, Bailus BJ, Melov S, Mooney SD et al: (2015) Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells. Stem Cell Reports, 5(6):1023-1038.

Neueder A, Bates GP. 2014. A Common gene expression signature in Huntington’s disease patient brain regions BMC Genomics 7:60 doi: 10.1186/s12920-014-0060-2.

Tourette C, Francesca F, Vazquez-Manrique RV, Orfila AM, Voisin J, Hernandez S, Offner O, Parker JA, Menet S, Kim J, Lyu J, Choi SH, Kerry Cormier K, Edgerly CK, Bordiuk OL, Smith K, Louise A, Halford M, Stacker S, Vert JP, Ferrante RJ, Lu W & Neri C (2014). The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity during the Early Phases of Mutant Huntingtin Pathogenicity. PLoS Biology, doi: 10.1371/journal.pbio.1001895.

Parmentier F, Lejeune FX, and Neri C (2013) Pathways to decoding the clinical potential of stress response FOXO-interaction networks for Huntington’s disease: of gene prioritization and context dependence. Frontiers in Aging Neuroscience, 5 : doi: 10.3389/fnagi.2013.00022.

FX Lejeune, L Mesrob, F Parmentier, C Bicep, R Vazquez, JA Parker, JP Vert, C Neri (2012). Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons. BMC Genomics 13 : 91 doi:10.1186/1471-2164-13-91.