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Tet1-mediated Epigenetic Programming Regulates Calcium Homeostasis and Stage-specific CNS Myelination and Regeneration

ABSTRACT: DNA hydroxymethylation by epigenetic modifiers TET dioxygenases is critical for gene transcription in various biological processes, however, its role in oligodendrocyte maturation and functions remain elusive. Here, we found that mice lacking Tet1 in the oligodendrocyte lineage exhibited hypomyelination in the CNS in the juvenile stage, leading to defects in action potential propagation, motor coordination, anxiety-like behavior and spatial memory capacities. Although the myelin deficiency recovered in adulthood, remyelination after cuprizone-induced demyelination was compromised in Tet1cKO mice. By integrating transcriptome and DNA methylation profiles, we identified a cohort of genes that were differentially regulated by Tet1 and hyperhydroxymethylation, including the genes associated with Ca2+ transportation. Tet1-deficient OPCs exhibited a reduction in [Ca2+] oscillations, while the agonists of calcium internal stores rescued the differentiation defect of Tet1-deficient OPCs. Thus, our results suggest that stage-specific Tet1-mediated epigenetic programming in oligodendrocytes maintain Ca2+ homeostasis for differentiation and regulate neuronal activities and myelin repair.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE122838 | GEO | 2019/11/20

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

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Tet1-mediated Epigenetic Programming Regulates Calcium Homeostasis and Stage-specific CNS Myelination and Regeneration

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