Background DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion. Results Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8–76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner. Conclusions Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease.

Hammo et al. show that a single dose of psilocybin rapidly and sustainably relieves both chronic pain and anxiodepressive-like behaviors in mice by restoring prefrontal activity through partial agonism at 5-HT2A and 5-HT1A receptors.

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

AbstractMotivation. Summary statistics from genome-wide association studies (GWAS) are widely used in fine-mapping and colocalization analyses to identify

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Circadian rhythms are endogenous oscillations that occur with a 24-h periodicity and support organismal homeostasis. While the role of the circadian clock in sy...

This study examines associations between fine particulate matter air pollution exposure, dementia severity, and dementia-associated neuropathologic change.

Pharmacological recovery of mitochondrial function improves blood-brain barrier function and cognition in 22q11.2 deletion syndrome, a risk factor for schizophrenia.

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Author summary All mammals have a unique class of genes that are crucial for normal growth, known as “imprinted genes,” where only one gene copy inherited from a parent is active. Imprinted genes are ...

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Preventing endosomal damage sensing or using lipids that create reparable endosomal holes reduces inflammation caused by RNA-lipid nanoparticles while enabling high RNA expression.

Based on 337 human kidney and plasma samples, the authors generate the first kidney pQTL dataset and explore novel risk loci that are relevant for cardio-kidney-metabolic health.

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

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