Open research questions in Epigenetics and DNA Methylation
1,090 gap statements mined from Epigenetics and DNA Methylation papers in our 7.9M-paper local library, which holds 4,282 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
There is a need to understand the link between epigenetic aging and cancer, - and to develop new biomarkers and therapeutic strategies that take into account the complex interplay between epigenomic changes, metabolic dysfunction, and inflammation. The current understanding of the epigenetic aging-cancer continuum is limited, and there is a need for further research to elucidate the underlying mechanisms.
One of the challenges is the complexity of the epigenetic modifications that contribute to type 2 diabetes. Another challenge is the limited understanding of the genetic risk of type 2 diabetes. The paper also highlights the challenge of developing effective therapeutic strategies that can modulate epigenetic signatures in type 2 diabetes.
The role of epigenetic signatures in type 2 diabetes: therapeutic advances and lifestyle interventions · 2026 · DOIThe study involves the analysis of complex biological samples, including vascular tissues and peripheral blood leukocytes. The researchers need to integrate their findings with lab-internal and publicly available epigenome-wide methylation datasets. There is a need to validate the findings in larger independent cohorts.
Tissue-specific moderate DNA methylation alterations featuring hypomethylation in microRNA regulatory regions associated with advanced carotid atherosclerosis · 2026 · DOIThe presence and distribution characteristics of 4acC in prokaryotes are unclear. There is a lack of methods to detect 4acC at single-base resolution.
Detection of N4-Acetylcytosine in Escherichia coli Using APOBEC3A-Mediated Deamination Sequencing · 2026 · DOIThe study faces challenges in terms of data quality, with the need for quality control procedures and filtering criteria related to coverage. The study faces challenges in terms of data analysis, with the need for complex statistical models to account for potential confounders.
Examination of DNA Methylation Patterns in Children Born Premature with Prenatal Tobacco Smoke Exposure · 2025 · DOIThe exact role of histone modifications in disease pathogenesis and progression is not fully understood. There is a need to comprehend the molecular underpinnings of aging through the framework of epigenetics.
An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions · 2024 · DOIThe lack of precise diagnostic tools and effective treatment options for chronic pain. Inadequate understanding of the temporal dynamics of DNA methylation during the transition from acute to chronic pain. Limited knowledge of the epigenetic mechanisms underlying chronic pain.
Traditional detection methods have notable limitations, as they cannot provide genomic localization information for 5hmC and lack specific sequence context.
The development of effective IDH inhibitors is challenging due to the complexity of the IDH pathway and the need to selectively target mutant IDH enzymes. The clinical trials of IDH inhibitors have been associated with side effects, such as indirect hyperbilirubinemia and thrombocytopenia.
Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy · 2024 · DOIThe current understanding of the roles of H3K9me3 writers, erasers, and readers in cancer immunotherapy is limited. There is a need to synthesize the available information on the influence of these proteins on the response to immunotherapy. The potential of targeting H3K9me3 writers, erasers, and readers as a strategy for improving cancer immunotherapy is not fully explored.
The current understanding of epigenetic alterations in neurodegenerative disorders is limited. There is a need to develop methodologies to enhance epigenetic research. The paper aims to address the gap in understanding the role of epigenetics in neurodegenerative disorders.
Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues · 2024 · DOIThe association between content on the Asthma&Allergy array and chronological GA and EGAA has not been evaluated alone or in the context of perinatal exposures.
Immune pathways and prenatal/perinatal environmental exposures contribute to epigenetic gestational age prediction and acceleration · 2026 · DOIDespite the overlapping roles, their relationship remains poorly understood, especially in the early stages of life, characterized by rapid growth and high cellular demands.
Although epigenetic alterations are common in CRC, the epigenetic changes that occur during colorectal carcinogenesis remain unclear.
NOS1 hypermethylation may participate in the colorectal cancer development and be associated with its prognosis · 2026 · DOIHowever, how oncogenic signaling pathways interface with the DNA methylation machinery remains poorly understood.
Aurora kinase a phosphorylates and stabilizes UHRF1 to maintain DNA methylation and prostate cancer cell survival · 2026 · DOIAlthough limited by a moderate sample size, our findings indicate a potential biological pathway linking mAge-related metabolic dysregulation that may provide insight into breast cancer risk.
Associations of breast DNA methylation–based measures of biological ageing with obesity-related breast cancer risk markers · 2026 · DOIFurther validation in larger independent cohorts, - Investigation of the causal relationship between DNA methylation and atherosclerosis, - Examination of the role of DNA methylation in other types…
Tissue-specific moderate DNA methylation alterations featuring hypomethylation in microRNA regulatory regions associated with advanced carotid atherosclerosis · 2026 · DOIThe study used a targeted candidate-gene approach rather than an unbiased genome-wide discovery strategy - The sample size was limited to 4 litters from each treatment group - The study was conducted in mice and may not be generalizable…
Early epigenetic alterations in cardiac tissue following perinatal sertraline exposure in mice · 2026 · DOIFurther exploration of the biological functions and evolutionary conservation of 4acC, - Investigation of the regulatory functions of 4acC in physiological and pathological…
Detection of N4-Acetylcytosine in Escherichia coli Using APOBEC3A-Mediated Deamination Sequencing · 2026 · DOIUnderstanding the temporal dynamics of DNA methylation during the transition from acute to chronic pain, - Developing targeted therapeutic interventions, - Exploring the specific genes or gene networks that could be targets to reverse the epigenetic landscape associated with chronic…
Small sample sizes were used in several studies, - Some studies lacked the power to identify significant epigenetic changes, - There are inconsistent findings between different miRNA studies, - Discrepant findings between studies analyzing the same brain…
Simultaneously studying genetics and epigenetics, - Investigating novel epigenetic therapies, - Further research on the role of non-coding RNAs…
The study was based on a phase 1/2 dose-escalation trial, - The sample size was limited to 345 patients for enasidenib and 258 patients for ivosidenib, - The study did not investigate the long-term effects of IDH…
Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy · 2024 · DOIFurther research and clinical trials are needed to fully explore the potential and determine the efficacy and safety of JIB-04 in humans - Future studies are required to elucidate the molecular mechanisms behind CDYL functioning - The consistency of LSD1 effects across different solid tumors must be validated, and potential side effects require a thorough examination to ensure the safety of LSD1…
Further studies are needed to fully elucidate the mechanisms underlying the effects of perinatal sertraline exposure on cardiac development - Research should investigate the long-term consequences of early epigenetic alterations in cardiac tissue - Studies should examine the potential for other SSRIs to exert similar…
Early epigenetic alterations in cardiac tissue following perinatal sertraline exposure in mice · 2026 · DOI
Most-cited papers in Epigenetics and DNA Methylation
- Integrative analysis of 111 reference human epigenomes · Nature · 2015 · 6,365 citations
- Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1 · Science · 2009 · 5,179 citations
- Human DNA methylomes at base resolution show widespread epigenomic differences · Nature · 2009 · 4,119 citations
- Metabolic regulation of gene expression by histone lactylation · Nature · 2019 · 4,027 citations
- Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing · Science · 2002 · 3,260 citations
- Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine · Science · 2011 · 3,112 citations
- Epigenetics in Cancer · New England Journal of Medicine · 2008 · 3,107 citations
- CpG-rich islands and the function of DNA methylation · Nature · 1986 · 2,888 citations
- DNA methylation-based classification of central nervous system tumours · Nature · 2018 · 2,802 citations
- Gene Silencing in Cancer in Association with Promoter Hypermethylation · New England Journal of Medicine · 2003 · 2,734 citations
Most recent work
- CpGPT: a Foundation Model for DNA Methylation · bioRxiv · 2026
- Environmental epigenetics: new horizons in redefining biological and health outcomes · Environment International · 2026
- Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort · Nature Aging · 2026
- A pan-cancer compendium of 1,294 plasma cell-free DNA methylomes and fragmentomes enabling multicancer detection · Nature Cancer · 2026
- The value of Protein Phosphatase Methylesterase 1 in diagnosis, prognosis and immunoregulation: from pan-cancer analysis to breast cancer verification · Frontiers in Immunology · 2026
- Leveraging epigenetic biomarker proxies for precision medicine · medRxiv · 2026
- Epigenetic remodeling during early embryonic development · Frontiers in Cell and Developmental Biology · 2026
- 5-methylcytosine and 5-hydroxymethylcytosine are synergistic biomarkers for early detection of colorectal cancer · Communications Medicine · 2026
- DNA methylation and prediction of biological age · Frontiers in Molecular Biosciences · 2026
- wgbstools : a computational suite for DNA methylation sequencing data analysis · Life Science Alliance · 2026
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