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 (NSC) cultures derived from embryonic midbrains greatly enhanced differentiation towards midbrain-type DA (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.

The epigenetic role of vitamin C in health and disease

“…In the midbrain of SLC23A2 +/− mouse embryos, the number of dopaminergic neurons is decreased. Ascorbate supplementation greatly enhances the differentiation of midbrain derived neural stem cell toward dopaminergic neurons, which is correlated with TET1 mediated 5hmC generation and Jmjd3 catalyzed loss of H3K27m3 [53]. Thus, it appears that ascorbate plays a role in dopaminergic neuron differentiation.…”

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…Likewise, the H3K27me3 specific demethylases Kdm6b and Utx (ubiquitously transcribed tetratricopeptide repeat, X alias Kdm6a) continue to be expressed in adult neurons. The activity of H3K27me3 specific demethylases is regulated by intracellular levels of α-ketoglutarate that fluctuate in response to neuronal activation [105]. Additionally, neuronal activation can directly phosphorylate histone H3 at Ser28 (H3S28p), leading to the displacement of PRC2 [106].…”

JMJD3 as an epigenetic regulator in development and disease

“…This was associated with increased H3K27 marks in the midbrain of aged mice, suggesting that JMJD3 plays a role in microglia polarization and may alter immune pathogenesis of Parkinson’s disease (Tang et al, 2014). Furthermore, in a subtype of neurons that is associated with Parkinson’s disease, the mid-brain type dopaminergic (DA) neurons, vitamin C enhances their differ entiation (He et al, 2014). Vitamin C decreases H3K27me3 marks on gene promoters in cells of the DA phenotype (He et al, 2014), suggesting that JMJD3 mediates their differentiation.…”

“…Furthermore, in a subtype of neurons that is associated with Parkinson’s disease, the mid-brain type dopaminergic (DA) neurons, vitamin C enhances their differ entiation (He et al, 2014). Vitamin C decreases H3K27me3 marks on gene promoters in cells of the DA phenotype (He et al, 2014), suggesting that JMJD3 mediates their differentiation. The involvement of JMJD3 was confirmed using Jmjd3 knockdown or Jmjd3 inhibition experiments, which demonstrated that H3K27me3 changes are essential for vitamin C-mediated mid-brain type DA neuron differentiation (He et al, 2014).…”

“…Vitamin C decreases H3K27me3 marks on gene promoters in cells of the DA phenotype (He et al, 2014), suggesting that JMJD3 mediates their differentiation. The involvement of JMJD3 was confirmed using Jmjd3 knockdown or Jmjd3 inhibition experiments, which demonstrated that H3K27me3 changes are essential for vitamin C-mediated mid-brain type DA neuron differentiation (He et al, 2014). In addition to Parkinson’s disease, JMJD3 has been implicated in Alzheimer’s disease.…”