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Nucleic Acids Res. 2020 Jan 10;48(1):184-199. doi: 10.1093/nar/gkz1093.

Discovery of a new predominant cytosine DNA modification that is linked to gene expression in malaria parasites.

Author information

1
Institut Pasteur, 75015 Paris, France.
2
CNRS ERL9195, 75015 Paris, France.
3
INSERM U1201, 75015 Paris, France.
4
Sorbonne Université, Ecole doctorale Complexité du Vivant ED515, F-75005 Paris, France.
5
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
6
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore.
7
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
8
Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, 75005 Paris, France.
9
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

DNA cytosine modifications are key epigenetic regulators of cellular processes in mammalian cells, with their misregulation leading to varied disease states. In the human malaria parasite Plasmodium falciparum, a unicellular eukaryotic pathogen, little is known about the predominant cytosine modifications, cytosine methylation (5mC) and hydroxymethylation (5hmC). Here, we report the first identification of a hydroxymethylcytosine-like (5hmC-like) modification in P. falciparum asexual blood stages using a suite of biochemical methods. In contrast to mammalian cells, we report 5hmC-like levels in the P. falciparum genome of 0.2-0.4%, which are significantly higher than the methylated cytosine (mC) levels of 0.01-0.05%. Immunoprecipitation of hydroxymethylated DNA followed by next generation sequencing (hmeDIP-seq) revealed that 5hmC-like modifications are enriched in gene bodies with minimal dynamic changes during asexual development. Moreover, levels of the 5hmC-like base in gene bodies positively correlated to transcript levels, with more than 2000 genes stably marked with this modification throughout asexual development. Our work highlights the existence of a new predominant cytosine DNA modification pathway in P. falciparum and opens up exciting avenues for gene regulation research and the development of antimalarials.

PMID:
31777939
PMCID:
PMC6943133
DOI:
10.1093/nar/gkz1093
[Indexed for MEDLINE]
Free PMC Article

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