Epigenetic changes in remethylation disorders: a novel target
Inherited disorders of remethylation represent inborn errors of folate and vitamin B12 metabolism. Clinically, patients show life threatening disease and have impaired neurological development. Since remethylation is required for the production of S-adenosylmethionine (SAM), the primary substrate for epigenetic methylation of DNA and histones, there is clear reason to expect the epigenome to be disturbed in these disorders. Further, given the importance of the epigenome to neuronal development, we suspect that epigenetic disturbance may contribute to neurological disease. Our project will examine whether neuronal differentiation is dependent on the affected pathways, and whether disturbed epigenetic modifications contribute to neurological dysfunction in these disorders. To do so, we will use induced pluripotent stem cell (iPSC)-to-neuron differentiation in vitro. This will be used to develop a better understanding of whether epigenomic disturbances throughout neuronal development can help predict disease progression and improve clinical treatments. Further, using patient material, we will identify whether individuals with remethylation disorders have altered global and loci-specific epigenetic status, whether this varies between patients, and whether this correlates to the overall disease state.
Publications
Kiessling E, Peters F, Ebner LJA, Merolla L, Samardzija M, Baumgartner MR, Grimm C, Froese DS. HIF1 and DROSHA are involved in MMACHC repression in hypoxia. Biochim Biophys Acta Gen Subj. 2022 Sep;1866(9):130175. doi: 10.1016/j.bbagen.2022.130175. Epub 2022 May 28. PMID: 35636712.
Forny P, Bonilla X, Lamparter D, Shao W, Plessl T, Frei C, Bingisser A, Goetze S, van Drogen A, Harshman K, Pedrioli PGA, Howald C, Poms M, Traversi F, Bürer C, Cherkaoui S, Morscher RJ, Simmons L, Forny M, Xenarios I, Aebersold R, Zamboni N, Rätsch G, Dermitzakis ET, Wollscheid B, Baumgartner MR, Froese DS. Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency. Nat Metab. 2023 Jan;5(1):80-95. doi: 10.1038/s42255-022-00720-8. Epub 2023 Jan 26. PMID: 36717752; PMCID: PMC9886552.
McCorvie TJ, Ferreira D, Yue WW, Froese DS. The complex machinery of human cobalamin metabolism. J Inherit Metab Dis. 2023 May;46(3):406-420. doi: 10.1002/jimd.12593. Epub 2023 Feb 8. PMID: 36680553.
Ramon C, Traversi F, Bürer C, Froese DS, Stelling J. Cellular and computational models reveal environmental and metabolic interactions in MMUT-type methylmalonic aciduria. J Inherit Metab Dis. 2023 May;46(3):421-435. doi: 10.1002/jimd.12575. Epub 2022 Nov 23. PMID: 36371683.
Mathis D, Koch J, Koller S, Sauter K, Flück C, Uldry AC, Forny P, Froese DS, Laemmle A. Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency. Mol Genet Metab Rep. 2024 Feb 23;39:101066. doi: 10.1016/j.ymgmr.2024.101066. PMID: 38425868; PMCID: PMC10900122.
Blomgren LKM, Huber M, Mackinnon SR, Bürer C, Baslé A, Yue WW, Froese DS, McCorvie TJ. Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase. Nat Commun. 2024 Apr 15;15(1):3248. doi: 10.1038/s41467-024-47174-y. PMID: 38622112; PMCID: PMC11018872.
Myszkowska J, Klotz K, Leandro P, Kruger WD, Froese DS, Baumgartner MR, Spiekerkoetter U, Hannibal L. Real-time detection of enzymatically formed hydrogen sulfide by pathogenic variants of cystathionine beta-synthase using hemoglobin I of Lucina pectinata as a biosensor. Free Radic Biol Med. 2024 Oct;223:281-295. doi: 10.1016/j.freeradbiomed.2024.07.031. Epub 2024 Jul 25. PMID: 39067625.
Büchler LR, Blomgren LKM, Bürer C, Zanotelli VRT, Froese DS. Evidence for interaction of 5,10-methylenetetrahydrofolate reductase (MTHFR) with methylenetetrahydrofolate dehydrogenase (MTHFD1) and general control nonderepressible 1 (GCN1). Biochimie. 2025 Mar;230:138-146. doi: 10.1016/j.biochi.2024.11.010. Epub 2024 Nov 19. PMID: 39571719.
Denley MCS, Straub MS, Marcionelli G, Güra MA, Penton D, Delvendahl I, Poms M, Vekeriotaite B, Cherkaoui S, Conte F, von Meyenn F, Froese DS, Baumgartner MR. Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria. Commun Biol. 2025 Mar 11;8(1):410. doi: 10.1038/s42003-025-07828-z. PMID: 40069408; PMCID: PMC11897345.