PreImplantation Factor Dictates Oligodendrocyte Differentiation by Modulating NCOR2 Methylation in H19 Dependent Manner.

Spinelli, Marialuigia; Surbek, Daniel; Schoeberlein, Andreina; Keller, Irene; Bordey, Angelique; Barnea, Eytan; Paidas, Michael; Müller, Martin (March 2019). PreImplantation Factor Dictates Oligodendrocyte Differentiation by Modulating NCOR2 Methylation in H19 Dependent Manner. Reproductive sciences, 26(Suppl 1), 107A-107A. Sage

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Introduction: Premature infants face multiple challenges including periventricular leukomalacia (PVL) and successful therapies are lacking. Oligodendrocyte Progenitor Cells (OPCs) give rise to myelin producing cells during brain development. Activation of dormant OPCs at the epigenetic level represents an attractive strategy. Long non-coding RNA H19 is a potential candidate to regulate epigenetic cell differentiation since it inhibits S-adenosylmethionine-dependent methyltransferases that methylate DNA at regulatory sites. Since synthetic PreImplantation Factor (sPIF) protects against multiple neuronal disorders, we posit that sPIF activates OPCs by tuning gene methylation dynamics through H19.
Methods: We treated OPCs MO13.13 cell line with sPIF (200nM; 48h) and assessed downstream differentiation markers by quantitative RT-PCR and Western blot. We performed H19 loss and gain of function studies and genome-wide methylation profiling. We used Two-tailed Student’s t-test and Mann-Whitney tests analysis. We considered p <0.05 as significant.
Results: sPIF increased expression of immature and mature oligodendrocyte markers (MBP, Claudin-11, CNPase, and Olig2) at gene and protein level and this was H19-dependent (Fig. 1A and B). Genome-wide methylation profiling identified the gene locus of the nuclear receptor co-repressor 2 (NCOR2) as H19 target (Fig. 1C). NCOR2 is a key regulatory cellular factor determining OPC`s fate. Consistently, sPIF`s induced OPCs differentiation was abolished in the presence of siNCOR2 (Fig. 1D).
Conclusion: sPIF dictates OPCs fate by de-methylation of NCOR2 in H19 dependent manner (Fig. 1E). Given that sPIF promotes myelination in animal models and FDA Fast Track designation of sPIF in First Human Clinical Trial, sPIF clinical trials to prevent PVL may be envisioned.

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