Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood
Authors: Lars Erichsen
Wardah Mahmood
Pauline Ott
Simeon Santourlidis
Marcelo L Bendhack
Wolfgang A Schulz
Mohamed Hassan
Johannes C Fischer
Marcos J Arauzo-Bravo
Journal: Scientific Reports (2020)
Discipline: Multidisciplinary
Keywords: LINE-1 hypomethylation; epigenetic biomarker; human aging; DNA methylation patterns; cell-free DNA
Affiliations: Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Department of Urology, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany., Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain., IKERBASQUE, Basque Foundation for Science, 48009, Bilbao, Spain., Department of Urology, University Hospital, Positivo University, Curitiba, Brazil., Department of Surgery, Tulane University School of Medicine, New Orleans, LA, 70112, USA., Institut National de La Santé Et de La Recherche Médicale, University of Strasbourg, 67000, Strasbourg, France., Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. .

Abstract:  LINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers. 

Retracted: Yes

PubPeer comments:
 Figures 2 and 5 were brought to my attention by a reader. * Blue and green boxes: The DNA markers from two independent gels in Figures 2 and 5 look more similar than expected. * Yellow boxes: the two cfDNA lanes in Figure 2A look similar to each other. That same lane also looks like one of the lanes in Figure 5 * Pink boxes: the two gDNA lanes in Figure 2A look similar to each other. That same lane also looks like one of the lanes in Figure 5 * In Figure 2B, the left sides of the excised regions looks repetitive ![file] , 
 #1 In addition, two of the  excised regions in panel 2B have repetitive elements in them that would not be expected if these were truly photos of excised agarose gels. ![file] , 
 Retraction, February 2022: https: www.nature.com articles s41598-022-07275-4  The Authors have retracted this article. After publication concerns were raised about duplication of lanes within Figure 2 and between Figure 2 and Figure 5. The Authors were no longer able to locate the original data underlying these figures. Of note, the article was published in December 2020, and the concerns were raised in January 2021, one month later. It is surprising that the authors could not find the original data already one month after publication. ,