Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2.

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

doi:10.1172/jci.insight.132335

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.

Highlights

Advances in obstetric and neonatal care have successfully increased survival rates of very premature infants, but the cost is the increase in preterm-specific brain injuries [1]
We found that synthetic PreImplantation Factor (sPIF) induced expression of the nuclear receptor corepressor 2 (NCOR2) via H19/S-adenosylhomocysteine hydrolase (SAHH)-mediated DNA demethylation
We found that in vitro sPIF affected oligodendrocyte differentiation markers by increasing expression of H19, leading to decreased SAHH activity and global DNA methylation changes

Summary

Introduction

Advances in obstetric and neonatal care have successfully increased survival rates of very premature infants, but the cost is the increase in preterm-specific brain injuries [1]. The majority of prematurity survivors face long-term neurodevelopmental disabilities, including cerebral palsy, motor deficits, or/and cognitive impairments that persist at least to young adulthood [2] The hallmark of this injury is inflammation and altered gliogenesis with resulting diffuse white matter damage [3, 4]. Neurogenesis and gliogenesis are precise spatially and temporally regulated processes, where neurons are generated in an inside-out fashion first, followed by the production of astrocytes and/or oligodendrocytes [5, 6] In line with this notion, the peak period of diffuse white matter injury occurrence (24–32 weeks of gestation) coincides with the highest presence of immature oligodendrocytes in the white matter [7, 8]. Targeting and modulating oligodendrocytes’ fate in an immature brain after injury is an attractive strategy but has remained elusive [9, 10]

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