N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation
Authors: Ye Wang
Li-Wa Shao
Guifang Jia
Chengchuan Ma
Rong Niu
Yong Peng
Aibin He
Ying Liu
Chuan-Yun Li
Tianxiao Huang
Chuan He
Wanqiu Ding
Journal: Nature cell biology (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: DNA methylation; 6mA; eukaryotes; epigenetic mark; transgenerational inheritance
Affiliations: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China., Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China., Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China., Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA., Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA., State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. .

Abstract:  N6-methyldeoxyadenine (6mA), a major type of DNA methylation in bacteria, represents a part of restriction-modification systems to discriminate host genome from invader DNA1. With the recent advent of more sensitive detection techniques, 6mA has also been detected in some eukaryotes2-8. However, the physiological function of this epigenetic mark in eukaryotes remains elusive. Heritable changes in DNA 5mC methylation have been associated with transgenerational inheritance of responses to a high-fat diet9, thus raising the exciting possibility that 6mA may also be transmitted across generations and serve as a carrier of inheritable information. Using Caenorhabditis elegans as a model, here we report that histone H3K4me3 and DNA 6mA modifications are required for the transmission of mitochondrial stress adaptations to progeny. Intriguingly, the global DNA 6mA level is significantly elevated following mitochondrial perturbation. N6-methyldeoxyadenine marks mitochondrial stress response genes and promotes their transcription to alleviate mitochondrial stress in progeny. These findings suggest that 6mA is a precisely regulated epigenetic mark that modulates stress response and signals transgenerational inheritance in C. elegans. 

Retracted: No

PubPeer comments:
 Recent work from lab of Dr. Eric Greer (who originally reported 6mA in worms) suggests that the  detection of 6mA in C. elegans and other metazoa can be explained by bacterial contamination and other experimental artifacts. This study should be viewed with extreme skepticism and re-evaluated. https: bmcgenomics.biomedcentral.com articles 10.1186 s12864-019-5754-6 , 
 Yet another well executed study showing that previous reports of 6mA in higher organisms (including this one) are artifactual: No evidence for DNA N6-methyladenine in mammals https: advances.sciencemag.org content 6 12 eaay3335 ,