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2013 ; 14
(5
): R46
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5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation
processes in primary human monocytes
#MMPMID23705593
Klug M
; Schmidhofer S
; Gebhard C
; Andreesen R
; Rehli M
Genome Biol
2013[May]; 14
(5
): R46
PMID23705593
show ga
BACKGROUND: Cytosine methylation is a frequent epigenetic modification
restricting the activity of gene regulatory elements. Whereas DNA methylation
patterns are generally inherited during replication, both embryonic and somatic
differentiation processes require the removal of cytosine methylation at specific
gene loci to activate lineage-restricted elements. However, the exact mechanisms
facilitating the erasure of DNA methylation remain unclear in many cases.
RESULTS: We previously established human post-proliferative monocytes as a model
to study active DNA demethylation. We now show, for several previously identified
genomic sites, that the loss of DNA methylation during the differentiation of
primary, post-proliferative human monocytes into dendritic cells is preceded by
the local appearance of 5-hydroxymethylcytosine. Monocytes were found to express
the methylcytosine dioxygenase Ten-Eleven Translocation (TET) 2, which is
frequently mutated in myeloid malignancies. The siRNA-mediated knockdown of this
enzyme in primary monocytes prevented active DNA demethylation, suggesting that
TET2 is essential for the proper execution of this process in human monocytes.
CONCLUSIONS: The work described here provides definite evidence that
TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine initiates
targeted, active DNA demethylation in a mature postmitotic myeloid cell type.