Epigenetic modulation of neurodegenerative process

Anne-Laurence BOUTILLIER
DR CNRS

Karine MERIENNE
DR CNRS

The risk of developing a neurodegenerative disease is increasing due to the extension of life expectancy and overall aging of the populations. This risk could be exacerbated by global deterioration in environmental quality. Thus, in the absence of appropriate care, neurodegenerative diseases might represent heavy socio-economic burden.

We aim to meet the challenge, investigating basic mechanisms underlying the neurodegenerative process and testing new therapeutic approaches. We aim to decipher the key mechanisms in two representative neurodegenerative diseases: Alzheimer’s disease and Huntington’s disease. These two diseases are complementary with respect to etiology, frequency and symptoms.

More specifically, we investigate how epigenetic regulations are perturbed in affected brain cells in these diseases. Epigenetic regulations define mechanisms that change the genetic program of a cell without altering its DNA sequence, but inducing reversible chemical changes in chromatin (e.g. histone acetylation), which ultimately affects its relaxation status. Epigenetic mechanisms drive cellular differentiation and the acquisition of specific cellular identity. They are also involved in cellular aging, causing epigenetic erosion leading to progressive loss of cellular identity and function. In addition, environmental factors influence epigenetic regulation, either positively by enhancing the fitness of an  organism, or negatively by inducing excessive cellular stress. In the brain, balanced regulation of these mechanisms enables adapted behavioral responses, to which learning and memory processes, for example, contribute. What is the relationship between epigenetic regulation and neurodegenerative mechanisms? We believe it is necessary to address this question to resolve the equation that links neurodegeneration to brain aging and cognitive impairment.

Combining state-of-the-art technologies, in particular multi-omics to map the epigenetic landscape at genome-wide scale and cell-type-specific levels in diseased brain tissues, with genetic tools, cellular imaging and behavioral testing, we aim to develop new conceptual frames to foster translational research on neurodegenerative diseases (e.g. using epigenetic modulators, improving cognitive epigenetic priming, promoting brain cell resilience, slowing down brain aging…)

Tzeplaeff L, Seguin J, Le Gras S, Megat S, Cosquer B, Plassard D, Dieterlé S, Paiva I, Picchiarelli G, Decraene C, Alcala-Vida R, Cassel JC, Merienne K, Dupuis L, Boutillier AL. Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes. Prog Neurobiol. 2023 Aug;227:102483.

Alcala Vida, R, Lotz C, Seguin J, Decraene C, Brulé B, Awada A, Bombardier A, Cosquer B, Pereira de Vasconcelos A, Brouillet E, Cassel JC, Boutillier AL, Merienne, K. Altered-activity-regulated H3K9 acetylation at TGF-beta signaling genes during egocentric spatial memory processing in Huntington’s disease mice. Prog. Neurobiol. 2022 Dec;219:102363. doi:10.1016/j.pneurobio. 2022.102363.

Borcuk C, Héraud C, Herbeaux K, Diringer M, Panzer É, Scuto J, Hashimoto S, Saido TC, Saito T, Goutagny R, Battaglia D, Mathis C. Early memory deficits and extensive brain network disorganization in the AppNL-F/MAPT double knock-in mouse model of familial Alzheimer’s disease. Aging Brain. 2022 Jun 2;2:100042. doi: 10.1016/j.nbas.2022.100042. eCollection 2022

Linard M, Ravier A, Mougué L, Grgurina I, Boutillier AL, Foubert-Samier A, Blanc F, Helmer C. Infectious Agents as Potential Drivers of α-Synucleinopathies. Mov Disord. 2022 Mar;37(3):464-477.

Paiva I, Cellai L, Meriaux C, Poncelet L, Nebie O, Saliou JM, Lacoste AS, Papegaey A, Drobecq H, Le Gras S, Schneider M, Malik EM, Müller CE, Faivre E, Carvalho K, Gomez-Murcia V, Vieau D, Thiroux B, Eddarkaoui S, Lebouvier T, Schueller E, Tzeplaeff L, Grgurina I, Seguin J, Stauber J, Lopes LV, Buée L, Buée-Scherrer V, Cunha RA, Ait-Belkacem R, Sergeant N, Annicotte JS, Boutillier AL*, Blum D*. Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription. J Clin Invest. 2022 Jun 15;132(12):e149371. *joint last authors

Alcala Vida, R., Seguin J, Lotz C,Molitor AM, Irastorza-Azcarate I, AwadaA, Karasu N, Bombardier A, Cosquer B, Skarmeta JLG, Cassel JC, Boutillier AL, Sexton T, Merienne, K. Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice. Nature Commun. 2021 Jan 13;12(1):364. doi: 10.1038/s41467-020-20605-2.

Pistono C, Zimmermann A, Morel C, Herbeaux K, Héraud C, Dumont-Kientzy S, Pevet P, Felder-Schmittbuhl MP, Mathis C. Major role of MT2 receptors in the beneficial effect of melatonin on long-term recognition memory in C57BL/6J male mice. Horm Behav. 2021 Nov;136:105076. doi: 10.1016/j.yhbeh.2021.105076. Epub 2021 Oct 9.

Wang XL, Kooijman S, Gao Y, Tzeplaeff L, Cosquer B, Milanova I, Wolff SEC, Korpel N, Champy MF, Petit-Demoulière B, Goncalves Da Cruz I, Sorg-Guss T, Rensen PCN, Cassel JC, Kalsbeek A, Boutillier AL*, Yi CX*. Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity. Mol Psychiatry. 2021 May 28. doi: 10.1038/s41380-021-01169-z *joint last authors

Alcalà-Vida R, Awada A, Boutillier AL, Merienne K. Epigenetic mechanisms underlying enhancer modulation of neuronal identity, neuronal activity and neurodegeneration. Neurobiol Dis. 2020 Oct 27;147:105155. doi: 10.1016/j.nbd.2020.105155.

Schueller E, Paiva I, Blanc F, Wang XL, Cassel JC, Boutillier AL*, Bousiges O.* Dysregulation of histone acetylation pathways in hippocampus and frontal cortex of Alzheimer’s disease patients. Eur Neuropsychopharmacol. 2020 Apr;33:101-116. *co-corresponding authors

Chantal Mathis (2019) The value of the object recognition paradigm in investigating animal models of Alzheimer’s disease: Advances and future directions, in. Ennaceur A and de Souza Silva M (Editors), Handbook of Object Novelty Recognition, Volume 26, Academic Press, pp. 307-330 https://doi.org/10.1016/B978-0-12-812012-5.00021-5

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. Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures. Cell Rep. 2019 Feb 26;26(9):2477-2493.e9. doi: 10.1016/j.celrep.2019.02.

Chatterjee S, Cassel R, Schneider-Anthony A, Merienne K, Cosquer B, Tzeplaeff L, Halder Sinha S, Kumar M, Chaturbedy P, Eswaramoorthy M, Le Gras S, Keime C, Bousiges O, Dutar P, Petsophonsakul P, Rampon C, Cassel JC, Buée L, Blum D, Kundu TK, Boutillier AL. Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med. 2018 Nov;10(11). pii: e8587.

Cès A, Burg T, Herbeaux K, Héraud C, Bott JB, Mensah-Nyagan AG, Mathis C.  Age-related vulnerability of pattern separation in C57BL/6J mice. Neurobiol Aging. 2018 Feb;62:120-129. doi: 10.1016/j.neurobiolaging.2017.10.013. Epub 2017 Oct 25.

Douchamps V, Mathis C. A second wind for the cholinergic system in Alzheimer’s therapy. Behav Pharmacol. 2017 Apr;28(2 and 3-Spec Issue):112-123.

Le Gras S, Keime C, Anthony A, Lotz C, De Longprez L, Brouillet E, Cassel JC, Boutillier AL, Merienne K. Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature. Sci Rep. 2017 Feb 22;7:42875. doi: 10.1038/srep42875.

Bott JB, Héraud C, Cosquer B, Herbeaux K, Aubert J, Sartori M, Goutagny R, Mathis C.  APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input. J Neurosci. 2016 Oct 5;36(40):10472-10486. doi: 10.1523/JNEUROSCI.1174-16.2016.

Achour M, Le Gras S, Keime C, Parmentier F, Lejeune FX, Boutillier AL, Néri C, Davidson I, Merienne K. Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington’s disease mice. Hum Mol Genet. 2015 Jun 15;24(12):3481-96. doi: 10.1093/hmg/ddv099.