Featured
-
-
Article
| Open Access
Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus
Gene-editing at the DM1 mutant locus revealed a fundamental difference between undifferentiated and differentiated cell states: abnormal epigenetic modifications cannot be repaired after differentiation.
- Tayma Handal
- , Sarah Juster
- & Rachel Eiges
-
Article
| Open Access
Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations
DNMT3A R882H and R882C are mutation hotspots in acute myeloid leukemia. This study describes the structural and functional consequences of the DNMT3A R882H/R882C mutations which can provide a strategy for therapy of the disease mutations.
- Jiuwei Lu
- , Yiran Guo
- & Jikui Song
-
Article
| Open Access
Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.
- Kosuke Yamaguchi
- , Xiaoying Chen
- & Pierre-Antoine Defossez
-
Article
| Open Access
A negative feedback loop between TET2 and leptin in adipocyte regulates body weight
The epigenetic regulation in adipocytes during obesity remains poorly understood. Here, the authors demonstrate a negative feedback loop between TET2, a DNA demethylation enzyme, and leptin, an adipokine, in adipocytes, unveiling a compensatory mechanism by which the body counteracts the metabolic dysfunction induced by obesity.
- Qin Zeng
- , Jianfeng Song
- & Tuo Deng
-
Article
| Open Access
Genetic control of DNA methylation is largely shared across European and East Asian populations
Most functional genomic resources have been based on individuals with European ancestry. Here, the authors perform DNA methylation quantitative trait locus (mQTL) analyses in 3,701 European and 2,099 East Asian individuals to identify thousands of genetic variants, a large degree of which are shared between the two populations.
- Alesha A. Hatton
- , Fei-Fei Cheng
- & Allan F. McRae
-
Article
| Open Access
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
-
Article
| Open Access
Integrative cross-omics and cross-context analysis elucidates molecular links underlying genetic effects on complex traits
Genetic effects on functionally related ‘omic’ traits often co-occur in relevant cellular contexts, such as tissues. Here, the authors introduce X-ING, an integrative analysis method for cross-omics, cross-context associations based on summary-level data. Application to quantitative trait locus analysis yields insights into complex disease/trait mechanisms.
- Yihao Lu
- , Meritxell Oliva
- & Lin S. Chen
-
Article
| Open Access
QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration
Here, the authors perform genome-wide mapping of DNA methylation and expression quantitative trait loci, revealing associations among genotype, epigenome and transcriptome, uncovering genes and gene-environment interactions contributing to age-related macular degeneration (AMD).
- Jayshree Advani
- , Puja A. Mehta
- & Anand Swaroop
-
Article
| Open Access
Extensive DNA methylome rearrangement during early lamprey embryogenesis
DNA methylation plays a major role in establishing cell identity, but the dynamics of DNA methylation patterns are highly variable across species. Here, the authors discover extensive DNA methylation reprogramming during embryonic development of the sea lamprey, a jawless fish with a distinctive, highly disordered methylome.
- Allegra Angeloni
- , Skye Fissette
- & Ozren Bogdanovic
-
Article
| Open Access
Epiallelic variation of non-coding RNA genes and their phenotypic consequences
This study uncovers abundant DNA methylation variations of non-coding RNA genes in the natural Arabidopsis population and shows the importance of epigenetic variations in plant phenotypic plasticity and diversity.
- Jie Liu
- & Xuehua Zhong
-
Article
| Open Access
Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Cigarette smoking is an established risk factor for inflammatory bowel disease. The authors suggest that smoking may affect the risk of Crohn’s disease and ulcerative colitis by modulating the DNA methylation status of the DNMT3A, LTA/TNF, and AHRR region, respectively.
- Han Zhang
- , Rahul Kalla
- & Xue Li
-
Article
| Open Access
Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ, COG6 and ZNF678.
- Anna Ulrich
- , Yukyee Wu
- & Christopher J. Rhodes
-
Article
| Open Access
Maternal dominance contributes to subgenome differentiation in allopolyploid fishes
Cyprinids fish species contain multiple subgenomes as a result of past duplications. Here, Xu et al. report new genomes of 21 cyprinid fish and conclude that observed subgenome dominance patterns are likely due to both maternal dominance and transposable element densities in each polyploid.
- Min-Rui-Xuan Xu
- , Zhen-Yang Liao
- & Hua-Hao Zhang
-
Article
| Open Access
5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression
The mechanism by which DNA methylation regulates female reproduction in insects is largely unknown. Here Zhao et al. demonstrate that the 5mC modification orchestrates timely choriogenesis and proper fertilization by preventing prolonged ftz-f1 expression in the German cockroach.
- Zheng Zhao
- , Liang Li
- & Chonghua Ren
-
Article
| Open Access
Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
-
Article
| Open Access
Nitric oxide controls shoot meristem activity via regulation of DNA methylation
The authors show that gaseous Nitric Oxide (NO) promotes transit amplifying cell fate in the Arabidopsis shoot meristem. NO acts by modifying AGO4-WUSCHEL protein interactions in stem cells, directly linking NO signaling with DNA methylation.
- Jian Zeng
- , Xin’Ai Zhao
- & Jan U. Lohmann
-
Article
| Open Access
OVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
-
Article
| Open Access
The rate of epigenetic drift scales with maximum lifespan across mammals
Epigenetic drift has been hypothesized to contribute to epigenetic clock signals and variation in lifespan across species. Here, the authors show that an empirical measure of epigenetic drift scales with maximum lifespan across four mammal species and accumulates in non-random genomic locations.
- Emily M. Bertucci-Richter
- & Benjamin B. Parrott
-
Article
| Open Access
Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Circulating cell-free DNA (cfDNA) has diagnostic potential, and clarifying its origins will aid in the minimally-invasive detection and monitoring of disease. Here, authors find that physiologically, megakaryocytes are major sources of cfDNA, while erythroblasts also release small amounts of cfDNA.
- Joshua Moss
- , Roni Ben-Ami
- & Yuval Dor
-
Article
| Open Access
DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples.
- Ashish Goyal
- , Jens Bauer
- & Christoph Plass
-
Article
| Open Access
Paternal DNA methylation is remodeled to maternal levels in rice zygote
Liu et al. show that zygotic remodelling of paternal DNA methylation is matched to maternal levels in hybrids and that parental-specific epigenomes are re-established during embryogenesis, highlighting genetic control of epigenetic inheritance.
- Qian Liu
- , Xuan Ma
- & Dao-Xiu Zhou
-
Article
| Open Access
TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.
- Elizabeth Heyes
- , Anna S. Wilhelmson
- & Bo T. Porse
-
Article
| Open Access
DNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues
Molecular tests that can determine the tissue of origin of cancers of unknown primary (CUP) are still needed. Here, the authors develop a DNA methylation profiling assay and a machine learning classifier to predict the origin of metastatic tumours in CUP patients using formalin-fixed, paraffin embedded samples.
- Shirong Zhang
- , Shutao He
- & Hongcang Gu
-
Article
| Open Access
Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells
Loss-of-function mutations in the chromatin remodelling protein HELLS result in humoral immune deficiency. Authors here show in a conditional knockout mouse model that HELLS controls the kinetics of a typical germinal center response by DNA methylation, its absence leading to either the appearance of memory-B cell markers or a metabolic state change typical of plasma cells.
- Clara Cousu
- , Eléonore Mulot
- & Sébastien Storck
-
Article
| Open Access
Epigenome-wide association analysis of infant bronchiolitis severity: a multicenter prospective cohort study
DNA methylation patterns that are associated with disease can reveal genes involved in disease etiology. Here, the authors identify blood DNA methylation signatures that are associated with bronchiolitis severity and play important roles in tissues, cells, and pathways.
- Zhaozhong Zhu
- , Yijun Li
- & Kohei Hasegawa
-
Article
| Open Access
Epigenetic inheritance is unfaithful at intermediately methylated CpG sites
Here the authors question the prevalent view of DNA methylation as a stably inherited epigenetic mark, revealing that the existing model does not apply when considering genomic loci that are intermediately methylated.
- Amir D. Hay
- , Noah J. Kessler
- & Anne C. Ferguson-Smith
-
Article
| Open Access
Downregulation of transposable elements extends lifespan in Caenorhabditis elegans
Transposable elements in somatic cells become increasingly mobile during ageing. Here, the authors show that in the nematode Caenorhabditis elegans, downregulation of transposable elements extends lifespan, and that their increases with age are coupled with progressively growing N6-adenine methylation in these genetic loci.
- Ádám Sturm
- , Éva Saskői
- & Tibor Vellai
-
Article
| Open Access
Extrachromosomal circular DNA and structural variants highlight genome instability in Arabidopsis epigenetic mutants
Epigenetic control of extrachromosomal circular DNA (eccDNA) compartment and the relationships between eccDNA and plant genome stability remain unclear. Here, the authors investigate eccDNA and structural variations in Arabidopsis epigenetic mutants to reveal the eccDNA repertoire and its impact on genome stability.
- Panpan Zhang
- , Assane Mbodj
- & Marie Mirouze
-
Article
| Open Access
DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood
Here the authors identify an association between methylation of the suppressor of cytokine signaling 3 (SOCS3) and height in children from India, Gambia and the UK.
- Prachand Issarapu
- , Manisha Arumalla
- & Stephen Owens
-
Article
| Open Access
A qPCR technology for direct quantification of methylation in untreated DNA
Analysis of DNA methylation usually requires a chemical or an enzymatic pretreatment step. Here, the authors report a PCR-based technology for the detection of DNA methylation in untreated DNA, and present analytical and clinical results from methylation analysis of the MGMT promoter.
- Kamilla Kolding Bendixen
- , Maria Mindegaard
- & Rasmus Koefoed Petersen
-
Article
| Open Access
The MOM1 complex recruits the RdDM machinery via MORC6 to establish de novo DNA methylation
It has generally been considered that MOM1, a transcriptional silencing factor in plants, mediated silencing is independent or downstream of DNA methylation. Here, the authors show that MOM1 complex recruits the RdDM machinery through MORC6 to establish de novo DNA methylation in Arabidopsis.
- Zheng Li
- , Ming Wang
- & Steven E. Jacobsen
-
Article
| Open Access
A cryo-EM structure of KTF1-bound polymerase V transcription elongation complex
Here the authors report the cryo-EM structure of transcription elongation complex comprising eukaryotic RNA polymerase V and its elongation factor KTF1. This work provides structural understanding for the unique function of the fifth member of eukaryotic RNA polymerases.
- Hong-Wei Zhang
- , Kun Huang
- & Yu Zhang
-
Article
| Open Access
Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction
Cleft lip and palate is a common birth defect thought to involve both genetic and environmental components in its etiology. Here they identify a mechanism involving inflammation and E-cadherin mutations that reduces neural crest migration, leading to craniofacial defects.
- Lucas Alvizi
- , Diogo Nani
- & Roberto Mayor
-
Article
| Open Access
Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation
The role of DNA methylation in early embryo development has been difficult to determine due to the functional redundancy of DNA methyltransferases. Here they develop an efficient base editing system that enables one-step generation of Dnmt-null embryos and show that DNA methylation-related miRNA suppression may be involved in gastrulation.
- Qing Li
- , Jiansen Lu
- & Jinsong Li
-
Article
| Open Access
meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
-
Article
| Open Access
Roles of adenine methylation in the physiology of Lacticaseibacillus paracasei
The bacterium Lacticaseibacillus paracasei is used in the food industry and as a probiotic. Here, the authors use multi-omics and high-throughput chromosome conformation capture analyses to investigate the roles of a type of DNA methylation (N6-methyladenine modification) in this organism.
- Jie Zhao
- , Meng Zhang
- & Wenyi Zhang
-
Article
| Open Access
Multi-omic underpinnings of epigenetic aging and human longevity
Here, the authors integrate genomic, bulk and single-cell transcriptomic, and metabolomic data sets to compare the biological underpinning of four epigenetic clocks and human longevity, offering novel insights into aging biology.
- Lucas A. Mavromatis
- , Daniel B. Rosoff
- & Falk W. Lohoff
-
Article
| Open Access
DNMT1 mutant ants develop normally but have disrupted oogenesis
The role of DNA methylation in insects is poorly understood. Here, the authors knock out the DNA methyltransferase DNMT1 in an ant and find no obvious effects on development, rather showing that this enzyme seems to play a crucial role during early oogenesis.
- Iryna Ivasyk
- , Leonora Olivos-Cisneros
- & Daniel J. C. Kronauer
-
Article
| Open Access
The methylation landscape of giga-genome and the epigenetic timer of age in Chinese pine
DNA methylation level declines during aging of mammals. Here, the authors report single-base resolution landscape of cytosine DNA methylation at different ages of Chinese pine and show that the global cytosine DNA methylation gradually increases as age progresses.
- Jiang Li
- , Fangxu Han
- & Shihui Niu
-
Article
| Open Access
An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.
- Veronica Davalos
- , Claudia D. Lovell
- & Eva Hernando
-
Article
| Open Access
Sequence terminus dependent PCR for site-specific mutation and modification detection
Rapid and facile detection of specific nucleic acid modifications could have numerous applications. Here the authors present Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) as a generic and accessible approach, and demonstrate proof-of-principle cancer biomarker detection.
- Gaolian Xu
- , Hao Yang
- & Hongchen Gu
-
Article
| Open Access
Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B
DNA methylation is a repressive modification that is essential for development. Here the authors reveal a critical role for DNA methylation in placental development during pregnancy. Failure to properly establish placental DNA methylation patterns compromises not only placental function, but embryo survival.
- Simon Andrews
- , Christel Krueger
- & Courtney W. Hanna
-
Article
| Open Access
Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.
- Carla L. Esposito
- , Ida Autiero
- & Annalisa Di Ruscio
-
Article
| Open Access
Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease
Approximately 40 percent of people with type 1 diabetes develop kidney disease, but the risk factors are not well understood. Here, the authors identify DNA methylation signatures associated with diabetic kidney disease, of which 21 biomarkers predict the development of kidney failure.
- Laura J. Smyth
- , Emma H. Dahlström
- & Amy Jayne McKnight
-
Article
| Open Access
DNA methylation-based classification of sinonasal tumors
Sinonasal tumour diagnosis can be complicated by the heterogeneity of disease and classification systems. Here, the authors use machine learning to classify sinonasal undifferentiated carcinomas into 4 molecular classe with differences in differentiation state and clinical outcome.
- Philipp Jurmeister
- , Stefanie Glöß
- & David Capper
-
Article
| Open Access
Structural basis for activation of DNMT1
DNMT1 is an essential for maintaining genomic DNA methylation. Here, we report the cryo-EM structure of DNMT1 bound to ubiquitinated H3 and hemimethylated DNA, revealing structural insight into the activation mechanism of DNMT1.
- Amika Kikuchi
- , Hiroki Onoda
- & Kyohei Arita
-
Article
| Open Access
Cell division drives DNA methylation loss in late-replicating domains in primary human cells
DNA methylation loss has been observed in aging tissues and cancers for decades. Researchers from Van Andel Institute have now provided experimental evidence that this process is directly driven by cell division.
- Jamie L. Endicott
- , Paula A. Nolte
- & Peter W. Laird
-
Article
| Open Access
Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.
- Sibo Zhao
- , Jia Li
- & Xiao-Nan Li
-
Article
| Open Access
DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
Combined and differential roles of ADD domains of DNMT3A and DNMT3L on DNA methylation landscapes in mouse germ cells