Nature Biotechnology, Published online: 15 May 2026; doi:10.1038/s41587-026-03130-3
Many long noncoding RNA–DNA binding peaks detected using common assays arise from technical artifacts.
Exercise as a multiscale recalibration of stress-related homeostatic balance
Chronic stress disrupts homeostasis in the brain and body, leading to anxiety, depression, and cardiovascular and metabolic dysfunction. Although exercise can counter these effects, the mechanisms are scattered across fields and not yet integrated. This review proposes a multi-scale framework. Exercise is not only stress-relieving; it is also a controllable challenge that can recalibrate the system when repeated bouts are matched by sufficient recovery and bioenergetic support. We propose that repeated exercise engages a stress response–adaptation–recovery cycle, in which peripheral signals from skeletal muscles, liver, adipose tissue and gut convey body metabolic state to the brain and are consolidated into durable plasticity only when mitochondrial capacity, substrate availability, and redox balance permit recovery. These signals pass through the blood-brain barrier and engage plasticity switches, including neurotrophic signals, epigenetic modification and metabolic coupling, thus stabilizing the neural circuits of threat appraisal, reward processing and contextual memory. By integrating these dimensions, we clarify how exercise can transform short-term physical stress into lasting resilience and provide direction for future research.
Epigenetic Markers Link Early-Onset Colon and Rectal Cancer to Specific Pesticide
Epigenetic markers linking cancers in young adults to pesticide exposure have been uncovered. Scientists from Spain found that specifically, the pesticide picloram was associated with a higher risk of early-onset colon and rectal cancer, providing another lead to the cause of this disturbing new trend.
Their research paper appeared in Nature Medicine and the lead author is Silvana C. E. Maas, PhD, Cancer Computational Biology Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona.
“This pesticide seems to have a role in early onset colorectal cancer [patients diagnosed before 50 years of age]. Cases of these have been in the last decades and the biology of the tumors (early onset vs. regular onset) is very similar. So the cause of the rise should be something external, the exposome,” senior author José A. Seoane, PhD, told Inside Precision Medicine. Seoane is head of cancer computational biology group, Vall d’Hebron Institute of Oncology, Centro Saturnino, Spain.
“The exposome is any exposure [environmental, life-style, habits, food, pollution, etc.] that affects us during our lifetime, including development,” he added.
Cancer in young adults is a relatively recent phenomenon, brought to attention by many disturbing personal stories, including that of Princess Kate, and some eye-opening statistics. Until now, age has been a top risk factor for cancer.
The incidence of colorectal cancer (CRC), in particular, is rising rapidly in people younger than 50 years and this increase parallels shifts in lifestyle and environmental factors (the exposome). But whether these are indeed linked to the development of early-onset CRC (EOCRC) remains unknown.
Since there are limited exposome data in most cancer cohorts, this team constructed weighted methylation risk scores as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC compared to late-onset CRC (LOCRC)—patients diagnosed at age 70+ years.
“We included in the analysis exposures associated with lifestyle, pollution and pesticides, including picloram. The results (different exposure patterns between early onset and late onset) shows that the early onset cancers have more signal of poor diet, smoking, and picloram,” said Seoane.
He added that, “Several pesticides were included in the study. We included different pesticides both in the methylation study and in the population study.”
The team’s analysis confirmed previously identified risk factors, including educational attainment, diet and smoking habits. In addition, they identified exposure to the herbicide picloram as a new risk factor in the discovery cohort. Those findings were replicated in a meta-analysis comprising nine CRC cohorts.
The team then analyzed population-based data from 94 U.S. counties over 21 years and validated the association between picloram use and EOCRC incidence. The association was still statistically significant, after adjusting for socioeconomic factors and other pesticide use.
This research highlights the potential role of the exposome in EOCRC risk, the authors write.
“We are studying how other exposure signals that were not included in this study could be associated with CRC and also other tumors and we are trying to elucidate the mechanisms of action of picloram,” Seoane said.
Other potential causes of EOCRC identified have been linked to diet and pollutants.
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Biomarker of Epigenetic Aging Could Signal Depression
Research led by New York University suggests a marker of epigenetic aging could be linked to depression.
The team found that accelerated aging of a type of white blood cell called a monocyte was significantly associated with the psychological and cognitive expressions of depression in a group of women with and without HIV.
“Depression is not a one-size-fits-all disorder—it can look really different from person to person, which is why it’s so important to consider varied presentations and not just a clinical label,” said lead researcher Nicole Beaulieu Perez, PhD, assistant professor at NYU Rory Meyers College of Nursing, in a press statement.
“Our study reveals unique biological underpinnings of mental health that are often obscured by broad diagnostic categories.”
As reported in The Journals of Gerontology Series A, the researchers analyzed blood samples and depression scores from 440 women, 261 living with HIV and 179 without, from the Women’s Interagency HIV Study. They tested women with HIV as people with this disease and others affecting the immune system are at greater risk of depression than the general public.
The team looked at biological aging using two epigenetic clocks: a broad multi-tissue clock and a monocyte-specific clock that measures chemical modifications to DNA in these cells.
Depression was measured using the CES-D questionnaire, which separates physical, bodily expressions of depression such as fatigue, appetite loss, and agitation from psychological and cognitive expressions of the disorder such as hopelessness, anhedonia, and feelings of failure.
Accelerated monocyte aging was significantly associated with the psychological and cognitive expressions of depression and with anhedonia specifically, even after adjusting for HIV status, race, and ethnicity. The broader multi-tissue Horvath clock showed no association with any depression domain, suggesting it is the monocyte-specific aging signal, not generalized biological aging, that tracks with mood and cognitive symptoms.
Diagnosis of depression relies largely on self-reported symptoms and not a specific physiological test. The finding that monocyte aging maps onto cognitive and mood symptoms rather than physical ones is counterintuitive, since monocytes are inflammatory cells that one might expect to track physical, inflammation-driven complaints like fatigue.
The study is small and cross-sectional, so causality cannot yet be established, but if the claims of the study were validated it could help to personalize treatment for depression in the future.
“The dynamics of monocyte aging and depression warrant further study to clarify mechanistic links,” conclude the authors.
“Our findings bring us a step closer to this goal of precision mental health care, especially for high-risk populations, by providing a biological framework that could guide future diagnosis and treatment,” adds Beaulieu Perez.
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Uncovering risk factors in the exposome for early-onset colorectal cancer
Nature Medicine, Published online: 30 April 2026; doi:10.1038/s41591-026-04369-8
The alarming rise in the incidence of colorectal cancer among younger individuals is probably due to environmental factors; epigenetic signatures of exposures may help uncover drivers of this trend, but questions remain.
Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation
Nature Neuroscience, Published online: 30 April 2026; doi:10.1038/s41593-026-02263-7
The authors identify glucose-derived conversion of citrate to acetyl-CoA upstream of histone acetylation as modulating the regional dynamics of oligodendrocyte progenitors, with extranuclear acetyl-CoA from other sources being used for myelination.
Obesity Leaves Lasting DNA Methylation Memory in Immune Cells
A new study suggests that obesity leaves a durable molecular imprint on the immune system, one that persists long after weight loss and may continue to influence disease risk. Researchers at the University of Birmingham report that key immune cells retain an “epigenetic memory” of obesity, potentially sustaining inflammation and metabolic dysfunction even after patients return to a healthy weight.
The findings, published in EMBO Reports, provide a mechanistic explanation for a long-standing clinical observation: that individuals who lose weight often remain at elevated risk for conditions such as type 2 diabetes, cardiovascular disease, and certain cancers.
Immune cells retain a “memory” of obesity
The study focuses on CD4+ helper T cells, central regulators of immune coordination. By analyzing patient samples across multiple cohorts, including individuals undergoing pharmacological weight loss, rare genetic obesity syndromes, and lifestyle interventions, the researchers identified persistent epigenetic modifications in these cells.
Specifically, obesity was associated with changes in DNA methylation, a process in which chemical tags are added to DNA and alter gene expression without changing the underlying sequence. These modifications effectively encode a molecular memory of prior metabolic state.
As explained by the authors, these epigenetic marks can persist for years after weight loss. “The findings suggest that short-term weight loss may not immediately reduce the risk of some disease conditions associated with obesity,” said Claudio Mauro, PhD, senior author of the study. Instead, the immune system appears to retain a record of past metabolic stress that continues to influence cellular behavior.
Persistence beyond weight loss
The durability of this imprint is striking. The study estimates that obesity-associated DNA methylation patterns in T cells may persist for five to ten years after successful weight reduction. This suggests that immune remodeling lags far behind metabolic normalization.
Supporting this, the team observed similar patterns across diverse experimental systems, including human clinical samples and mouse models of diet-induced obesity. Together, these data point to a conserved biological mechanism rather than a transient or context-specific effect.
This persistent immune memory may help explain why relapse and long-term complications are common in obesity. As noted by Belinda Nedjai, PhD, of Queen Mary University of London, “the immune system retains a molecular record of past metabolic exposures, which may have implications for long-term disease risk and recovery.”
Disruption of cellular housekeeping and aging
At the functional level, the epigenetic changes identified in T cells appear to disrupt two critical biological processes: autophagy and immune senescence.
Autophagy, the process by which cells degrade and recycle damaged components, is essential for maintaining cellular health. The study suggests that obesity-associated DNA methylation impairs this pathway, reducing the cell’s ability to clear waste and maintain homeostasis.
In parallel, the researchers observed effects on immune aging, or senescence. Dysregulated T cells exhibited features of premature aging, potentially contributing to chronic inflammation and reduced immune resilience.
Together, these alterations could create a persistent pro-disease environment, even after weight loss. This reframes obesity not simply as a reversible metabolic state, but as a condition capable of inducing long-term immune reprogramming.
Implications for treatment strategies
The findings have direct implications for how obesity is managed clinically. If immune dysfunction persists for years after weight loss, then short-term interventions may be insufficient to fully restore health.
Instead, sustained weight maintenance—and potentially additional therapies targeting immune reprogramming—may be required. Mauro noted that “ongoing weight management following loss will see the ‘obesity memory’ slowly fade,” though this process may take years.
The study also points to potential therapeutic strategies. Drugs such as SGLT2 inhibitors, already used in diabetes treatment, may help accelerate the reversal of these epigenetic changes by reducing inflammation and promoting clearance of dysfunctional cells.
Rethinking obesity as a chronic immuno-metabolic disease
Beyond its immediate clinical implications, the study contributes to a broader conceptual shift in how obesity is understood. Rather than being defined solely by excess adiposity, obesity emerges as a condition that induces lasting systemic changes, particularly within the immune system.
As Andy Hogan, PhD, of Maynooth University emphasized, “obesity is a chronic progressive and relapsing disease,” and these findings help explain the biological basis of that persistence.
By identifying an epigenetic “memory” within immune cells, the work highlights a previously underappreciated dimension of metabolic disease: its capacity to reprogram immune function over the long term.
Looking ahead
The discovery of obesity-induced immune memory raises new questions about reversibility and intervention. Can these epigenetic marks be actively erased? And if so, how can therapies be designed to accelerate immune recovery?
Future research will likely focus on targeting these pathways directly, with the aim of restoring normal immune function and reducing long-term disease risk.
For now, the findings underscore a key message: losing weight is only part of the story. Fully reversing the biological impact of obesity may require sustained intervention—not just at the metabolic level, but at the level of the immune system itself.
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Epigenetic Mapping in Pancreatic Cells Identifies New Diabetes Target
Researchers at Lund University in Sweden have conducted the first study looking at epigenetic changes associated with type 2 diabetes in alpha and beta pancreatic cells. Published today in Nature Metabolism, their findings show that the ONECUT2 gene plays a key role in the development of type 2 diabetes by altering insulin production.
“The study shows that many genes central to insulin and glucagon production are regulated by differences in DNA methylation,” says Charlotte Ling, PhD, professor of epigenetics at Lund University and lead author of the study. “It has made it possible, for the first time, to describe detailed, cell-specific epigenetic patterns.”
The number of people living with diabetes is rapidly increasing worldwide, with approximately 95% of cases attributed to type 2 diabetes. This condition develops gradually and is characterized by a reduced ability to use insulin effectively, leading to elevated blood sugar levels. Over time, high blood sugar can lead to a range of complications that significantly impact the patient’s quality of life.
Lifestyle factors like diet and physical activity are major drivers of this condition; however, genetics can also contribute to the development of type 2 diabetes, increasing the risk for some people over others. While genome- and epigenome-wide studies on diabetes have identified genetic and epigenetic mechanisms involved in type 2 diabetes, previous epigenetics studies had only looked at whole tissues and none had investigated epigenetic changes within specific cell types that are involved in blood sugar regulation.
Ling’s team focused on alpha and beta pancreatic cells, which secrete insulin and glucagon hormones, respectively, to regulate blood sugar levels. By analyzing hundreds of thousands of cells from 24 people, with and without diabetes, the researchers created the most detailed epigenetics mapping of pancreatic cells to date. This allowed them to discover over 22,000 regions in nearly 8,000 genes that were differentially methylated between alpha and beta cells.
“Here, for the first time, we show exactly which regions regulate insulin and glucagon production through DNA methylation, which gives us the opportunity to develop future treatments based on epigenetics,” says Ling.
They then used CRISPR epigenetic editing to alter DNA methylation around the genes encoding for insulin and glucagon, which revealed that levels of the ONECUT2 transcription factor were elevated in beta cells from type 2 diabetes patients. This epigenetic upregulation was found to impair the ability of beta cells to release insulin, which in turn disrupted glucose regulation and reduced energy production within the cell.
Based on their findings, the researchers developed a web tool intended as a comprehensive resource available to researchers investigating the impact of age, sex, and type 2 diabetes on DNA methylation and gene expression in alpha and beta cells.
“We now want to understand which of these changes can actually be reversed, and whether this can help beta cells regain their function in diabetes,” says Ling. “A key aspect is to see whether the effects of editing DNA methylation can be sustained in the cell over time.”
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Transcriptomic and phenotypic convergence of neurodevelopmental disorder risk genes in vitro and in vivo
Nature Neuroscience, Published online: 24 April 2026; doi:10.1038/s41593-026-02247-7
By studying 23 neurodevelopmental disorder genes across model systems and brain cell types, the authors uncovered shared downstream effects that converge on synaptic biology, epigenetic regulation and mitochondrial function.
AACR 2026: Cancers of Unknown Primary Identified by DNA Methylation AI Model
SAN DIEGO – Researchers from Kindai University in Japan have developed a machine learning model that accurately predicts the origin of diverse cancer types in patients with cancers of unknown primary (CUP) by analyzing CpG-based DNA methylation. Results showed that the model correctly identified the cancer type in about 95% of cases in the test cohort, and achieved 87% accuracy when applied to an independent validation cohort from 31 cases representing 17 different cancer types. The work was presented at the American Association for Cancer Research (AACR) Annual Meeting.
“Our findings suggest that DNA-based approaches can help identify where a cancer may have started, even when the original tumor is not visible,” said Marco A. De Velasco, PhD, a faculty member in the department of genome biology at Kindai University in Japan.
CUP are metastatic malignancies in which the primary cancer site could not be identified. These cancers are often associated with poorer outcomes, as patients are typically treated with broad, nonspecific chemotherapy regimens rather than therapies targeted to a specific cancer type.
Approximately only 15-20% of patients with CUP show features that allow site-specific therapies. Patients receiving site-directed therapy can survive up to 24 months, compared with six to nine months for those receiving standard treatment.
Patterns in tumor biology, such as gene activity or chemical modifications to DNA, can differ between cancer types and persist even after the cancer has spread and guide development of these therapies. While some methods have shown promise, they have yet to demonstrate clear survival benefits in clinical trials.
The model was developed using methylation data from nearly 7,500 patients with 21 different cancer types obtained from The Cancer Genome Atlas Program and other public datasets. Using machine learning, the researchers identified CpG methylation and built methylation profiles that were associated with different tumor types.
Del Velasco emphasized that the study achieved high accuracy in predicting the origin of diverse cancer types using a small subset of DNA markers, about 1,000 CpG regions selected from hundreds of thousands across the genome. “This is important because it shows that we can simplify complex molecular data while still maintaining strong predictive performance,” he said.
As a limitation, the model was developed using cancers with known origins, rather than true CUP. Testing in CUP patients is important to understand how well the model performs in clinical settings. Additionally, not all tumors are easily accessible for genetic testing, particularly tumors in advanced stage. Looking ahead, the authors aim to adapt and evaluate the model using blood-based biopsy to analyze circulating tumor DNA instead of relying on DNA from tissue samples.
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