The inability to digest lactose, due to lactase nonpersistence, is a common trait in adult mammals, except in certain human populations that exhibit lactase persistence. It is not known how the ...lactase gene is dramatically downregulated with age in most individuals but remains active in some individuals. We performed a comprehensive epigenetic study of human and mouse small intestines, by using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. Epigenetically controlled regulatory elements accounted for the differences in lactase mRNA levels among individuals, intestinal cell types and species. We confirmed the importance of these regulatory elements in modulating lactase mRNA levels by using CRISPR-Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements, because lactase-persistence and lactase-nonpersistence DNA haplotypes demonstrated markedly different epigenetic aging. Thus, genetic factors enable a gradual accumulation of epigenetic changes with age, thereby influencing phenotypic outcome.
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Circadian rhythmicity governs a remarkable array of fundamental biological functions and is mediated by cyclical transcriptomic and proteomic activities. Epigenetic factors are also involved in this ...circadian machinery; however, despite extensive efforts, detection and characterization of circadian cytosine modifications at the nucleotide level have remained elusive. In this study, we report that a large proportion of epigenetically variable cytosines show a circadian pattern in their modification status in mice. Importantly, the cytosines with circadian epigenetic oscillations significantly overlap with the cytosines exhibiting age-related changes in their modification status. Our findings suggest that evolutionary advantageous processes such as circadian rhythmicity can also contribute to an organism's deterioration.
Maintenance of physiological circadian rhythm plays a crucial role in human health. Numerous studies have shown that disruption of circadian rhythm may increase risk for malignant, psychiatric, ...metabolic, and other diseases.
Extending our recent findings of oscillating cytosine modifications (osc-modCs) in mice, in this study, we show that osc-modCs are also prevalent in human neutrophils. Osc-modCs may play a role in gene regulation, can explain parts of intra- and inter-individual epigenetic variation, and are signatures of aging. Finally, we show that osc-modCs are linked to three complex diseases and provide a new interpretation of cross-sectional epigenome-wide association studies.
Our findings suggest that loss of balance between cytosine methylation and demethylation during the circadian cycle can be a potential mechanism for complex disease. Additional experiments, however, are required to investigate the possible involvement of confounding effects, such as hidden cellular heterogeneity. Circadian rhythmicity, one of the key adaptations of life forms on Earth, may contribute to frailty later in life.
Dynamic patterns of cytosine-5 methylation and successive hydroxylation are part of epigenetic regulation in eukaryotes, including humans, which contributes to normal phenotypic variation and disease ...risk. Here we present an approach for the mapping of unmodified regions of the genome, which we call the unmethylome. Our technique is based on DNA methyltransferase-directed transfer of activated groups and covalent biotin tagging of unmodified CpG sites followed by affinity enrichment and interrogation on tiling microarrays or next generation sequencing. Control experiments and pilot studies of human genomic DNA from cultured cells and tissues demonstrate that, along with providing a unique cross-section through the chemical landscape of the epigenome, the methyltransferase-directed transfer of activated groups-based approach offers high precision and robustness as compared with existing affinity-based techniques.
Abstract
Motivation
Biological rhythmicity is fundamental to almost all organisms on Earth and plays a key role in health and disease. Identification of oscillating signals could lead to novel ...biological insights, yet its investigation is impeded by the extensive computational and statistical knowledge required to perform such analysis.
Results
To address this issue, we present DiscoRhythm (Discovering Rhythmicity), a user-friendly application for characterizing rhythmicity in temporal biological data. DiscoRhythm is available as a web application or an R/Bioconductor package for estimating phase, amplitude and statistical significance using four popular approaches to rhythm detection (Cosinor, JTK Cycle, ARSER and Lomb-Scargle). We optimized these algorithms for speed, improving their execution times up to 30-fold to enable rapid analysis of -omic-scale datasets in real-time. Informative visualizations, interactive modules for quality control, dimensionality reduction, periodicity profiling and incorporation of experimental replicates make DiscoRhythm a thorough toolkit for analyzing rhythmicity.
Availability and implementation
The DiscoRhythm R package is available on Bioconductor (https://bioconductor.org/packages/DiscoRhythm), with source code available on GitHub (https://github.com/matthewcarlucci/DiscoRhythm) under a GPL-3 license. The web application is securely deployed over HTTPS (https://disco.camh.ca) and is freely available for use worldwide. Local instances of the DiscoRhythm web application can be created using the R package or by deploying the publicly available Docker container (https://hub.docker.com/r/mcarlucci/discorhythm).
Supplementary information
Supplementary data are available at Bioinformatics online.
Reproducibility is crucial for scientific progress, yet a clear research data analysis workflow is challenging to implement and maintain. As a result, a record of computational steps performed on the ...data to arrive at the key research findings is often missing. We developed Scikick, a tool that eases the configuration, execution, and presentation of scientific computational analyses. Scikick allows for workflow configurations with notebooks as the units of execution, defines a standard structure for the project, automatically tracks the defined interdependencies between the data analysis steps, and implements methods to compile all research results into a cohesive final report. Utilities provided by Scikick help turn the complicated management of transparent data analysis workflows into a standardized and feasible practice. Scikick version 0.2.1 code and documentation is available as supplementary material. The Scikick software is available on GitHub (https://github.com/matthewcarlucci/scikick) and is distributed with PyPi (https://pypi.org/project/scikick/) under a GPL-3 license.
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Epigenetic age oscillates during the day Koncevičius, Karolis; Nair, Akhil; Šveikauskaitė, Aušrinė ...
Aging Cell,
July 2024, Volume:
23, Issue:
7
Journal Article
Peer reviewed
Open access
Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions ...display a 24‐h periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset. While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24‐h periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time‐of‐day for obtaining accurate estimates of epigenetic age.
In this article, we report an intriguing finding: epigenetic age predictions display a 24‐h periodicity. Numerous epigenetic clocks consistently showed that human blood cells appeared much younger around midnight compared to noon. This finding emphasizes the importance of considering the time of‐day when estimating epigenetic age.
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The cover image is based on the Short Communication Epigenetic age oscillates during the day by Karolis Koncevičius et al., https://doi.org/10.1111/acel.14170
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10.
The 10th annual MLSP competition: Third place Koncevicius, Karolis
2014 IEEE International Workshop on Machine Learning for Signal Processing (MLSP),
2014-Sept.
Conference Proceeding
The goal of the MLSP 2014 competition was to automatically detect subjects with schizophrenia based on multimodal features derived from magnetic resonance imaging data. This report summarizes the 3rd ...place solution with the final ROC area score of 0.91282.
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