5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes

Genome Biology

Michael Rehli¹  Reinhard Andreesen²  Claudia Gebhard¹  Sandra Schmidhofer¹  Maja Klug³ 

[1] Department of Internal Medicine III, University Hospital Regensburg, D-93042 Regensburg, Germany;Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany;German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany

关键词: differentiation;    active DNA demethylation;    Epigenetics;   

Others  :  866677
DOI  :  10.1186/gb-2013-14-5-r46

 received in 2012-10-10, accepted in 2013-05-26,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Klug et al.; licensee BioMed Central Ltd.

【 图 表 】

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