Study of the links between the dysregulations of metabolism and histone post-translational modifications in Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by a triad of motor, cognitive and psychiatric symptoms usually starting during adulthood, and resulting from the degeneration of striatal neurons. Increasing evidence indicates that altered energy metabolism and rewired epigenetic regulation of gene expression, largely mediated by dynamic histone post-translational modifications (PTMs), count among mechanisms early impaired in HD striatal neurons. We want to study dysregulations of histone PTMs in HD, to better understand how they contribute to a perturbed gene expression program and lead to accelerated aging of striatal neurons. More specifically, we will investigate the interplay between altered energy metabolism and impairment of histone PTMs in HD striatal neurons, to identify new targets/pathways for disease-modifying intervention.

We first aim to obtain detailed maps of histone PTMs, especially of methylations, acetylation and the recently described lactylation, which might be critical in the HD brain. Indeed, these PTMs are tightly regulated by the metabolic status of the cells. We will use proteomics which is the best suited approach to identify and quantify multiple protein PTMs. We consider working on the striatum of wild-type mice as controls and two mouse models of HD at various stages of disease, to assess evolution of histone PTMs and metabolism with aging. Additionally, to get a dynamic view of the links between metabolic and epigenetic imbalance in HD, we will inject intraperitoneally HD mice and controls with 13C-glucose and analyze over a time course the incorporation of 13C into histone PTMs.

Finally, we wish to address the question of the possible production, in the vicinity of chromatin, of metabolites used for histone PTMs in striatal cells. Acetyl-CoA, the precursor for histone lysine acetylation, has been shown to be locally produced in the nucleus, by either acetyl-CoA synthetase 2 (ACSS2), ATP-citrate lyase (ACLY) or the pyruvate dehydrogenase complex. Regarding lactylation, it is currently unknown where, and by which enzymes, the pool of lactate used for modifying histone lysines by lactylation is produced. ACSS2 is a very good candidate, as it can catalyze the production of acyl-CoA molecules from the corresponding short chain fatty acids (SCFA). We will use epigenomics (ChIPseq or CUT&tag) to get the genomic distribution of ACSS2 and ACLY and compare it to distributions of acetyl and lactyl histone marks. 

The PhD student will spend most of the time in the team EDyP (Studying the Dynamics of Proteomes), in CEA Grenoble. EDyP has a long-standing experience in proteomics, is equipped with latest-generation mass spectrometry instruments and develops dedicated informatics programs to interpret proteomics data. The PhD student will be directed by Delphine Pflieger, who has gained ten years experience in the proteomic characterization of histones and their multiple post-translational modifications. The PhD student will also have the opportunity to spend time in the team of Karine Merienne (Laboratoire Neurosciences Cognitives et Adaptatives, UMR7364 CNRS/Strasbourg University, Strasbourg), who is a specialist in the study of epigenetic dysfunction in Huntington's disease and would co-direct this PhD. He/she will be involved there in the production and interpretation of genomics data, with the aim to establish the genome-wide distribution of selected histone marks and metabolic enzymes, and to integrate these datasets with gene expression data.  

Relevant references:

Crespo M, Damont A, Blanco M, Lastrucci E, Kennani SE, Ialy-Radio C, Khattabi LE, Terrier S, Louwagie M, Kieffer-Jaquinod S, Hesse AM, Bruley C, Chantalat S, Govin J, Fenaille F, Battail C, Cocquet J, Pflieger D. Multi-omic analysis of gametogenesis reveals a novel signature at the promoters and distal enhancers of active genes. Nucleic Acids Res. 2020 May 7;48(8):4115-4138.  doi: 10.1093/nar/gkaa163.

Hseiky A, Crespo M, Kieffer-Jaquinod S, Fenaille F, Pflieger D. Small Mass but Strong Information: Diagnostic Ions Provide Crucial Clues to Correctly Identify Histone Lysine Modifications. Proteomes. 2021 Apr 23;9(2):18. doi: 10.3390/proteomes9020018.

Blanco M, El Khattabi L, Gobé C, Crespo M, Coulée M, de la Iglesia A, Ialy-Radio C, Lapoujade C, Givelet M, Delessard M, Seller-Corona I, Yamaguchi K, Vernet N, Van Leeuwen F, Lermine A, Okada Y, Daveau R, Oliva R, Fouchet P, Ziyyat A, Pflieger D, Cocquet J. DOT1L regulates chromatin reorganization and gene expression during sperm differentiation. EMBO Rep. 2023 Apr 26;e56316. doi: 10.15252/embr.202256316.

Alcalá-Vida R, Seguin J, Lotz C, Molitor AM, Irastorza-Azcarate I, Awada A, 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. Nat. Commun. 2021 Jan 13;12(1):364. doi: 10.1038/s41467-020-20605-2.

Alcalá-Vida R, Lotz C, Brulé B, Seguin J, Decraene C, 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 memory in Huntington's disease. Prog. Neurobiol. 2022 Dec;219:102363. doi: 10.1016/j.pneurobio.2022.102363.

Concrete experiments planned and relevant profile of the PhD candidate

Using dedicated biochemical protocols, you will prepare histone protein samples from mice striata, and process them for their proteomic analysis on latest-generation MS instruments (e.g. Q-Exactive HF or Ascend). You will interpret the produced data using specialized software (Mascot, the in-house developed program Proline, and Skyline). In a second part of the PhD work, you will have the opportunity to be involved in studying the genome-wide distribution of histone PTMs and of metabolic enzymes by ChIP-seq or CUT-tag, followed by informatics analysis of the acquired data. Candidates to this PhD project should have a training in biochemistry, ideally in proteomics (at least on the theoretical level), be endowed with solid analytical reasoning, and be interested in learning the bioinformatics handling of proteomics and/or genomics data.