Genome-Wide Alteration of 5-Hydroxymethylcytosine in Hypoxic-Ischemic Neonatal Rat Model of Cerebral Palsy.

Yunpeng Zhang,Long Chen,Yaodong Zhang,Jimin Shi,Jihong Zhang,Danmei Chen,Chao Gao,Wei Fan,Bing Li,Cuiting Wang

doi:10.3389/fnmol.2019.00214

Abstract

Cerebral palsy (CP) is a neurodevelopmental disorder usually occurring early in life and persisting through the whole life. Several risk factors, including perinatal hypoxia-ischemia (HI), may contribute to occurrence of CP in preterm infants. DNA hydroxymethylation has been shown to play an important role in neurodevelopment and neurodegenerative disorders. However, the effect of DNA hydroxymethylation in CP remains unknown. The aim of this study is to explore whether and how DNA hydroxymethylation is involved in CP pathogenesis. We observed that overall 5-hydroxymethylcytosine (5hmC) abundance in the cortex of the temporal lobe of rat pups was decreased significantly after hypoxic-ischemic injury, and the reduced expression of Tet1 and Tet2 enzymes might be responsible for this change. Identified differential hydroxymethylation regions (DhMRs) were richly involved in multiple signaling pathways related to neuronal development and function. Furthermore, we found that reduced 5hmC modification on the DhMRs-related genes were accompanied by decrease of their mRNA expression levels. These results suggest that 5hmC modifications are involved in the CP pathogenesis and may potentially serve as a new therapeutic target.

Highlights

Cerebral palsy is the most common cause for childhood mortality which shows a worldwide prevalence being around 2 to 3.5 death per 1000 live births
We assessed the impact of neonatal HI brain injury on the righting reflex to determine whether there were any deficits in this fundamental nervous reflex
In addition to the proven genes whose expression levels are accompanied by a decrease in the level of hydroxymethylation, we found that 88 differential genes are known to be involved in the pathogenesis of Cerebral palsy (CP)

Summary

Introduction

Cerebral palsy is the most common cause for childhood mortality which shows a worldwide prevalence being around 2 to 3.5 death per 1000 live births. A lot of basic science studies has Abbreviations: CNS, central nervous system; CP, cerebral palsy; CpG, cytosine guanine; DhMRs, differential hydroxymethylation regions; FDR, false discovery rate; GO, gene ontology; HI, hypoxia-ischemia; hMeDIP, hydroxymethylated DNA immunoprecipitation; hMeDIP-seq, hydroxymethylated DNA immunoprecipitation sequencing; HOMER, hypergeometric optimization of motif enrichment; 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; MACS, model-based analysis of ChIP-Seq; MWM, Morris water maze; Tet, ten-eleven translocation. Among all the known epigenetic mechanisms, DNA methylation is one of the most extensively studied and plays a critical role in chromatin structure remolding, transcriptional repression of genes, and embryonic development (Li et al, 1992; Zemach et al, 2010; Jursch et al, 2013). DNA methylation on the fifth carbon of cytosine (5mC) is essential for neurogenesis (Wang et al, 2016), learning and memory (Yu et al, 2011), and synaptic plasticity (Munoz et al, 2016) in mammalian CNS

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