Juozas Gordevičius

Van Andel Institute

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Artūras Petronis

Centre for Addiction and Mental Health

Gabriel Oh

Centre for Addiction and Mental Health

Miki Susic

Centre for Addiction and Mental Health

Daniel E. Groot

Centre for Addiction and Mental Health

Algimantas Kriščiūnas

Vilnius University

Viviane Labrie

Van Andel Institute

Rafal Kustra

University of Toronto

Kim N.

BC Cancer Agency

Anthony M. Joshua

The Kinghorn Cancer Centre

Steven Yip

Occupational Cancer Research Centre

Cooperative Institutions

Van Andel Institute

Vilnius University

University of Toronto

Centre for Addiction and Mental Health

University of California, Los Angeles

Michigan State University

Universidad Nacional de La Plata

Biochemistry Research Institute of La Plata

Harvard University

University of Helsinki

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medRxiv (Cold Spring Harbor Laboratory) (2021)

Ao‐Ji Xie Elizabeth Ensink Peipei Li Juozas Gordevičius Lee Marshall

Abstract Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson’s disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia , and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are linked to epigenetic changes in leucocytes and neurons from PD patients, and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain gastrointestinal and psychiatric disorders, which could be relevant for their epidemiological linkage.

Gut–brain axis

Bisulfite sequencing

10.1101/2021.09.17.21263343

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aPEAR: an R package for autonomous visualization of pathway enrichment networks

Bioinformatics (2023)

Ieva Kerševičiūtė Juozas Gordevičius

The interpretation of pathway enrichment analysis results is frequently complicated by an overwhelming and redundant list of significantly affected pathways. Here, we present an R package aPEAR (Advanced Pathway Enrichment Analysis Representation) which leverages similarities between the pathway gene sets and represents them as a network of interconnected clusters. Each cluster is assigned a meaningful name that highlights the main biological themes in the experiment. Our approach enables an automated and objective overview of the data without manual and time-consuming parameter tweaking.The package aPEAR is implemented in R, published under the MIT open-source licence. The source code, documentation, and usage instructions are available on https://gitlab.com/vugene/aPEAR as well as on CRAN (https://CRAN.R-project.org/package=aPEAR).

Tweaking

R package

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Code (set theory)

Pathway Analysis

10.1093/bioinformatics/btad672

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Citations (26)

Additional file 3 of Identification of fetal unmodified and 5-hydroxymethylated CG sites in maternal cell-free DNA for non-invasive prenatal testing

Figshare (2020)

Juozas Gordevičius Milda Narmontė Povilas Gibas Kotryna Kvederavičiūtė Vita Tomkutė

Additional file 3: Table S2. List of the identified DMRs with AUC = 1.

Cell-free fetal DNA

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10.6084/m9.figshare.13120833

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Tet2loss suppress α-synuclein pathology by stimulating ciliogenesis

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Emmanuel Quansah Naman Vatsa Elizabeth Ensink Jaycie Brown T. Delle Cave

ABSTRACT There are no approved treatments that slow Parkinson’s disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro . Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and rescued the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo . Our findings demonstrate the crucial role of Tet2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

Ciliogenesis

Epigenome

10.1101/2024.08.02.606408

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Supplementary Table 5. from Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

Juozas Gordevičius Algimantas Kriščiūnas Daniel E. Groot Steven Yip Miki Susic

List of significant AA-DVPs.

Abiraterone acetate

Table (database)

Abiraterone

10.1158/1078-0432.22470312

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Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging

Nature Communications (2018)

Gabriel Oh Sasha B. Ebrahimi Matthew Carlucci Aiping Zhang Akhil Nair

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.

Cytosine

Epigenesis

10.1038/s41467-018-03073-7

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Citations (57)

Supplementary Data from Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

Juozas Gordevičius Algimantas Kriščiūnas Daniel E. Groot Steven Yip Miki Susic

Supplementary methods, supplementary table legends, and all supplementary figures.

Abiraterone acetate

Abiraterone

Table (database)

10.1158/1078-0432.22470327.v1

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Small extracellular vesicles from young mice prevent frailty, improve healthspan and decrease epigenetic age in old mice

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Jorge Sanz‐Ros Cristina Mas‐Bargues Daniel Monleón Juozas Gordevičius Robert T. Brooke

Summary Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

Senescence

Extracellular Vesicles

10.1101/2021.07.29.454302

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Data from Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

Juozas Gordevičius Algimantas Kriščiūnas Daniel E. Groot Steven Yip Miki Susic

<div>AbstractPurpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20% to 40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance.Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients.Results: Thirty cytosines showed significant modification differences (FDR Q < 0.05) between AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA treatment, but such variation returned to initial levels in the later phases of treatment.Conclusions: Our findings provide a list of potential biomarkers for predicting AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients. Clin Cancer Res; 24(14); 3317–24. ©2018 AACR.</div>

Abiraterone acetate

10.1158/1078-0432.c.6527517

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Multiomics Analysis of Neuroblastoma Cells Reveals a Diversity of Malignant Transformations

Frontiers in Cell and Developmental Biology (2021)

Milda Narmontė Povilas Gibas Kristina Daniūnaitė Juozas Gordevičius Edita Kriukienė

Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system that exhibits significant variation in the stage of differentiation and cell composition of tumors. Global loss of DNA methylation and genomic 5-hydroxymethylcytosine (5hmC) is a hallmark of human cancers. Here, we used our recently developed single-base resolution approaches, hmTOP-seq and uTOP-seq, for construction of 5hmC maps and identification of large partially methylated domains (PMDs) in different NB cell subpopulations. The 5hmC profiles revealed distinct signatures characteristic to different cell lineages and stages of malignant transformation of NB cells in a conventional and oxygen-depleted environment, which often occurs in tumors. The analysis of the cell-type-specific PMD distribution highlighted differences in global genome organization among NB cells that were ascribed to the same lineage identity by transcriptomic networks. Collectively, we demonstrated a high informativeness of the integrative epigenomic and transcriptomic research and large-scale genome structure in investigating the mechanisms that regulate cell identities and developmental stages of NB cells. Such multiomics analysis, as compared with mutational studies, open new ways for identification of novel disease-associated features which bring prognostic and therapeutic value in treating this aggressive pediatric disease.

Epigenomics

Cell type

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10.3389/fcell.2021.727353

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Citations (7)