Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain

By Junjie U. Guo, Yijing Su, C. Zhong, Guo-li Ming, Hongjun Song. 2011

1,370 citations recorded by the source corpus.

SUMMARY Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base-excision repair pathway. While expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammal cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals.

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “…promote BDNF and FGF1 expression in mature dentate granule cells in response to neuronal activation and deletion of Gadd45b reduces activity-induced proliferation of neural precursors and dendritic growth of newborn neurons in the adult hippocampus (Guo et al., 2011a; Ma et al., 2009).”
DNA Methylation and Its Basic Function (2013, background): “However, in slowly dividing and nondividing cells such as the brain, gene body methylation is not associated with increased gene expression (Aran et al, 2011; Guo et al, 2011a, b; Xie et al, 2012).”
DNA methylation presents distinct binding sites for human transcription factors (2013, methodology): “Sanger bisulfite sequencing was performed as previously described (Guo et al., 2011; Ma et al., 2009).”
Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair (2011, unknown): “During gene activation in the adult mouse brain, demethylation by TET1-mediated hydroxylation of 5meC to 5hmC was promoted by AID/Apobec deaminases, in a process that generates 5-hydroxymethyluracil (5hmU) and ultimately requires BER, although the specific glycosylases involved were not identified (”
Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, unknown): “, 2011), and demethylation pathways through these modified cytosines have been shown (Cortellino et al., 2011; Guo et al., 2011; He et al., 2011; Maiti and Drohat, 2011; Zhang et al., 2012).”
Editing DNA methylation in the mammalian genome (2016, unknown): “DNA replication-independent active demethylation has been proposed to operate in postmitotic neurons (Guo et al., 2011; Martinowich et al., 2003).”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, unknown): “…excision of oxidized 5mC bases, including removal of 5hmU (deamination product Cell 156, January 16, 2014 ª2014 Elsevier Inc. 49 of 5hmC) (Guo et al., 2011) or 5fC/5caC (He et al., 2011;Maiti and Drohat, 2011), may result in abasic sites that are further repaired by BER to restore…”
Global Epigenomic Reconfiguration During Mammalian Brain Development (2013, background): “Given the evidence that hmC can be an intermediate in an active DNA demethylation pathway (16, 17), high-resolution analysis of the genomic distribution of hmC is needed to understand its role in the control of DNA methylation dynamics through brain development.”
DNA Demethylation Dynamics (2011, background): “In mammals, the process is more complex, as no glycosylases have been identified that act directly on 5mC or 5hmC. Recently, an intermediate step, deamination, has been suggested to precede BER in mammalian DNA demethylation (Cortellino et al., 2011; Guo et al., 2011).”