S-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome

Abstract

SUMMARY Axonal myelination is essential for rapid saltatory impulse conduction in the nervous system, and malformation or destruction of myelin sheaths leads to motor and sensory disabilities. DNA methylation is an essential epigenetic modification during mammalian development, yet its role in myelination remains obscure. Here, using high-resolution methylome maps, we show that DNA methylation could play a key gene regulatory role in peripheral nerve myelination and that S-adenosylmethionine (SAMe), the principal methyl donor in cytosine methylation, regulates the methylome dynamics during this process. Our studies also point to a possible role of SAMe in establishing the aberrant DNA methylation patterns in a mouse model of diabetic neuropathy, implicating SAMe in the pathogenesis of this disease. These critical observations establish a link between SAMe and DNA methylation status in a defined biological system, and provides a novel mechanism that could direct methylation changes during cellular differentiation and in diverse pathological situations.

Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

“…DNA methylation in proliferating progenitors has been shown to prevent untimely differentiation and to guarantee faithful transmission of genomic information from mother to daughter cells during replication (Fan et al, 2005; Probst et al, 2009; Sen et al, 2010; Varela-Rey et al, 2014). To begin characterizing the role of DNA methylation in oligodendrocyte lineage cells, we quantified 5-methylcytosine (5-mC) in developing white matter tracts during embryonic and postnatal development.…”

“…An example is the apoptotic elimination of neural stem cells and mitotic neuroblasts lacking Dnmt1 (Fan et al, 2001; Hutnick et al, 2009; Milutinovic et al, 2003). In contrast, inhibiting DNA methylation in astrocytes or Schwann cells is associated with precocious onset of differentiation, due to the unmasking of critical transcriptional regulatory sites in differentiation genes (Fan et al, 2005; Takizawa et al, 2001; Varela-Rey et al, 2014). In this study, we show that ablation of Dnmt1 in the oligodendrocyte lineage does not result in apoptosis or precocious myelination, but causes growth arrest of oligodendrocyte progenitors (OPC) and a severely disrupted patterns of alternative splicing with activation of an endoplasmic reticulum (ER) stress response, which precludes differentiation and results in severe and clinically symptomatic hypomyelination.…”

Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2

“…After 15 strokes with a Dounce homogenizer, samples were centrifuged at 18,000 ϫ relative centrifugal force (rcf) for 10 min at 4°C. Pellets were washed with 1 ml of micrococcal nucleases (MNase) digestion buffer (0.32 M sucrose; 50 mM Tris-HCl, pH 7.5; 4 mM MgCl 2 ; 1 mM CaCl 2 ; protease inhibitor mixture) as described previously (Umlauf et al, 2004). After pelleting insoluble material by centrifugation, samples were resuspended in 200 l of MNase digestion buffer and incubated with 1 l (2000 gel units) of MNase (New England Biolabs, M0247) for 7 min at 37°C.…”

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

“…The maintenance of the differentiated and quiescent state of hepatocytes is highly dependent of one carbon metabolism, pathway that must be finely tuned to preserve central cellular processes as lipid homeostasis (6), epigenetic regulation (7), cell growth and apoptosis (8), stem cell programming, (9) and axonal myelinization (10). One carbon metabolism integrates a complex network of enzymatic reactions leading to the synthesis of pivotal biomolecules, including, among others, proteins, DNA, polyamines, folates, glutathione, and S-adenosylmethionine (SAMe), the main alkylating agent in living cells (11) and is recognized as the nexus of intermediary metabolism and epigenetic regulation (12).…”