title: Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner.
abstract: Intracellular Vitamin C (VC) is maintained at high levels in the developing brain by the activity of sodium-dependent VC transporter 2 (Svct2), suggesting specific VC functions in brain development. A role of VC as a cofactor for Fe(II)-2-oxoglutarate-dependent dioxygenases has recently been suggested. We show that VC supplementation in neural stem cell cultures derived from embryonic midbrains greatly enhanced differentiation toward midbrain-type dopamine (mDA) neurons, the neuronal subtype associated with Parkinson's disease. VC induced gain of 5-hydroxymethylcytosine (5hmC) and loss of H3K27m3 in DA phenotype gene promoters, which are catalyzed by Tet1 and Jmjd3, respectively. Consequently, VC enhanced DA phenotype gene transcriptions in the progenitors by Nurr1, a transcription factor critical for mDA neuron development, to be more accessible to the gene promoters. Further mechanism studies including Tet1 and Jmjd3 knockdown/inhibition experiments revealed that both the 5hmC and H3K27m3 changes, specifically in the progenitor cells, are indispensible for the VC-mediated mDA neuron differentiation. We finally show that in Svct2 knockout mouse embryos, mDA neuron formation in the developing midbrain decreased along with the 5hmC/H3k27m3 changes. These findings together indicate an epigenetic role of VC in midbrain DA neuron development.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea.
authors.forename: Xi-Biao
authors.initials: XB
authors.lastname: He
authors.forename: Mirang
authors.initials: M
authors.lastname: Kim
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Yi
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Taeho
authors.initials: T
authors.lastname: Kim
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Lee
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: Shilpy
authors.initials: S
authors.lastname: Dixit
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D049308:Dioxygenases / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000601821:TET1 protein, rat; D049308:Dioxygenases; D056484:Jumonji Domain-Containing Histone Demethylases; C000655037:Kdm6b protein, rat; D001205:Ascorbic Acid
keywords: 5hmC; Dopamine neuron; Fetal midbrain; Jmjd3; Vitamin C