Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2
Marialuigia Spinelli, Celiné Boucard, Sara Ornaghi, Andreina Schoeberlein, Keller Irene, Daniel Coman, Fahmeed Hyder, Longbo Zhang, Valérie Haesler, Angelique Bordey, Eytan Barnea, Michael Paidas, Daniel Surbek, Martin Mueller
Marialuigia Spinelli, Celiné Boucard, Sara Ornaghi, Andreina Schoeberlein, Keller Irene, Daniel Coman, Fahmeed Hyder, Longbo Zhang, Valérie Haesler, Angelique Bordey, Eytan Barnea, Michael Paidas, Daniel Surbek, Martin Mueller
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Research Article Neuroscience Therapeutics

Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2

Abstract

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes’ fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.

Authors

Marialuigia Spinelli, Celiné Boucard, Sara Ornaghi, Andreina Schoeberlein, Keller Irene, Daniel Coman, Fahmeed Hyder, Longbo Zhang, Valérie Haesler, Angelique Bordey, Eytan Barnea, Michael Paidas, Daniel Surbek, Martin Mueller

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Figure 2

sPIF/H19 modulates oligodendrocyte differentiation markers by demethylation of Ncor2.

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sPIF/H19 modulates oligodendrocyte differentiation markers by demethylat...
MO3.13 cells were transfected with vector (Vec), H19-containing plasmid (pH19), or sPIF (200 nM) and after 48 hours analyzed. (A) We measured S-adenosylhomocysteine hydrolase (SAHH) and (B) performed global genome methylation analysis. One specific sequence of the differentially methylated region–amplified (DMR-amplified) Ncor2 intron region with reduced methylated cytosine is highlighted in red. Numbers at the beginning and end of the sequence mark positions of the indicated nucleotides in the chromosome. The number above in red indicates the percentage of methylation in Vec compared with treatment (pH19 or sPIF; n = 3 each group). (C) We confirmed the specific hypomethylation site (as indicated in B) using quantitative methylation-specific PCR (QMSP) analysis. We measured Ncor2 expression at mRNA and protein levels (representative Western blots) after pH19 transfection (D). We confirmed Olig2 and Mbp induction using pH19 (D) and Ncor2 silencing in (E). (F) We measured mature and immature oligodendrocyte expression markers after sPIF (200 nM) treatment and specific siNCOR2 transfection. (G) These markers were measured after Ncor2 overexpression (G) as well. (H) Proposed model of sPIF to modulate oligodendrocyte fate by H19-induced hypomethylation of Ncor2. Single comparisons to Ctrl were made using a 2-tailed Student’s t test or Mann-Whitney test with Bonferroni’s correction. *P < 0.025; **P < 0.005; ***P < 0.0005. The levels of Ctrl and siCtrl were arbitrarily set to 1. Protein levels are presented after normalization to actin. Each experiment was conducted at least 3 times.