Epigenomes

Background: Graft-derived cell-free DNA (gdcfDNA) analysis has shown promise as a non-invasive tool for monitoring organ health following solid organ transplantation. A number of gdcfDNA analysis techniques have been described; however, the majority rely on sequencing or prior genotyping to detect donor-recipient mis-matched genetic polymorphisms. Differentially methylated regions of DNA can be used to identify the tissue-of-origin of cell-free DNA (cfDNA) fragments. In this study, we aimed to directly compare the performance of gdcfDNA monitoring using graft-specific DNA methylation analysis and donor-recipient genotyping techniques in a pilot cohort of clinical samples from patients post-liver transplantation. Results: 7 patients were recruited prior to LT, 3 developed early, biopsy-proven TCMR in the first 6 weeks post-LT. gdcfDNA was successfully quantified in all samples using both approaches. There was a high level of technical correlation between results using the two techniques (Spearman testing, rs = 0.87, p < 0.0001). gdcfDNA levels quantified using the genotyping approach were significantly greater across all timepoints in comparison to the tissue-specific DNA methylation-based approach: e.g., day 1 post-LT median 31,350 copies/mL (IQR 6731-64,058) vs. 4133 copies/mL (IQR 1100-8422), respectively. Qualitative trends in gdcfDNA levels for each patient were concordant between the two assays. Acute TCMR was preceded by significant elevations in gdcfDNA as quantified by both techniques. Elevations in gdcfDNA, using both techniques, were suggestive of TCMR in this pilot study with a 6- and 3-day lead-time prior to histological diagnosis in patients 1 and 2. Conclusions: Both the graft-specific methylation and genotyping techniques successfully quantified gdcfDNA in patients post-LT with statistically significant concordance. A direct comparison of these two techniques is not only important from a technical perspective for orthogonal validation, but significantly adds weight to the evidence that gdcfDNA monitoring reflects the underlying biology. Both techniques identified LT recipients who developed acute TCMR, with several days lead-time in comparison to conventional diagnostic workflows. Whilst the two assays performed comparably, gdcfDNA monitoring based on graft-specific DNA methylation patterns in cfDNA offers major practical advantages over the donor-recipient genotyping, and hence enhances the potential to translate this emerging technology into clinical practice.

Daniel R. A. Cox

Tess McClure

Fan Zhang

Boris Ka Leong Wong

Adam Testro

Su Kah Goh

Vijayaragavan Muralidharan

Alexander Dobrovic

Graft-Derived Cell-Free DNA Quantification following Liver Transplantation Using Tissue-Specific DNA Methylation and Donor-Specific Genotyping Techniques: An Orthogonal Comparison Study

Background/Objectives: People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH. Methods: We conducted an epigenome-wide association study (EWAS) on 892 African American male PWH from the Veterans Aging Cohort Study, examining BMI associations with DNAm using linear mixed models, adjusting for covariates, including soluble CD14. We compared our results with BMI-associated DNAm markers from non-HIV individuals and developed a methylation risk score (MRS) for BMI using machine learning and a cross-validation approach. Results: We identified four epigenome-wide significant CpG sites, including one in the RAP1B gene, indicating shared and unique BMI-related epigenetic markers between PWH and non-HIV individuals. The constructed BMI MRS explained approximately 19% of the BMI variance in PWH. Conclusions: DNAm markers and MRS are significantly linked to BMI in PWH, suggesting shared and distinct molecular mechanisms with non-HIV populations. These insights could lead to targeted interventions to reduce cardiometabolic disease risks in PWH under ART.

Nanzha Abi

Alexandra Young

Pradeep Tiwari

Junyu Chen

Chang Liu

Qin Hui

Kaku So-Armah

Matthew S. Freiberg

Amy C. Justice

Ke Xu

Marta Gwinn

Vincent C. Marconi

Yan V. Sun

Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV

HIV感染者体重指数的全基因组表观遗传和甲基化风险评分分析

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal’s health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, activate, or silence genes at different stages of development and/or in response to different environmental stimuli. However, little is known about postnatal metabolic programming in Bos indicus. Therefore, this study aimed to compare the DNA methylation profile of Nellore animals submitted to conventional and early weaning and to correlate the findings with genes differentially expressed in the Longissimus thoracis skeletal muscle of Bos indicus cattle. Methods: For this, we used Reduced Representation Bisulfite Sequencing (RRBS) and RNA-Sequencing techniques to prospect differentially methylated genes (DMGs). Results: A total of 481 differentially methylated regions were identified, with 52% (250) being hypermethylated and 48% (231) hypomethylated. Functional enrichment analysis of 53 differentially methylated and differentially expressed genes was performed. The main enriched terms and pathways were associated with 3′-5′-cyclic adenosine monophosphate (cAMP) signaling, which presents the upregulated adenylate cyclase 3 (ADCY3) gene and significatively hypomethylated in the promoter region. Alterations in cAMP signaling are involved in numerous processes, many of them related to lipid metabolism. The relative differential expression of key genes of this pathway demonstrates the relationship between cAMP signaling and de novo lipogenesis. Conclusions: These findings suggest an important role of postnatal metabolic programming through DNA methylation mechanisms in determining fat deposition in beef.

Gustavo Tinoco

Gustavo Russo

Rogério Curi

Marcelo Vicari

Paloma Melo

Isabella Souza

Juliana Torrecilhas

Philipe Moriel

Welder Baldassini

Luis Chardulo

Otávio Neto

Guilherme Pereira

DNA Imprinting and Differentially Expressed Genes in Longissimus thoracis Muscle of Bos indicus Submitted to Early Weaning Management

印度瘤牛背最长肌DNA印记及早期断奶管理下差异表达基因

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase in variability in males (FDR &lt; 0.05) but none in females. In females, we found a significantly higher proportion of CpGs showing increased variability with age among nominally significant (p &lt; 0.05) CpGs under inactivation, but not among CpGs escaping inactivation. Survival analysis showed a slight trend of correlation by directional change in the variable CpGs with mortality in males. Compared with females, the male X-chromosome can be more vulnerable to epigenetic instability during aging.

Qihua Tan

Hikmat Alo

Marianne Nygaard

Mette Sørensen

Alisa Saleh

Jonas Mengel-From

Kaare Christensen

Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins

男性与女性双胞胎X染色体上年龄依赖的DNA甲基化变异性

Background/Objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors on DNA methylation remain underexplored. This study aimed to quantify these effects using a novel approach. Methods: A cohort study was conducted on healthy monozygotic twins to evaluate the influence of environmental stimuli on DNA methylation. We developed the Environmental Factor Index (EFI) to identify methylation sites showing statistically significant changes in response to environmental stimuli. We analyzed the identified sites for associations with disorders, DNA methylation markers, and CpG islands. Results: The EFI identified methylation sites that exhibited significant associations with genes linked to various disorders, particularly cancer. These sites were overrepresented on CpG islands compared to other genomic features, highlighting their regulatory importance. Conclusions: The EFI is a valuable tool for understanding the molecular mechanisms underlying disease pathogenesis. It provides insights into the development of preventive and therapeutic strategies and offers a new perspective on the role of environmental factors in epigenetic regulation.

Yoichi Takenaka

Mikio Watanabe

Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins

环境因素指数（EFI）：一种评估同卵双胞胎DNA甲基化环境影响强度的新方法

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for gene expression and cellular integrity, particularly with a focus on H3K36 and H3K4 methylation marks. H3K36 tri-methylation plays a crucial role in maintaining chromatin integrity by facilitating the recruitment of the Rpd3S histone deacetylase (HDAC) complex, which helps restore closed chromatin states following transcription and prevents cryptic initiation within gene bodies. In parallel, crosstalk between H3K4 di-methylation and histone ubiquitylation and sumoylation is critical for recruiting the Set3 HDAC complex, which maintains low histone acetylation levels in gene bodies and further suppresses cryptic transcription. Therefore, by elucidating these regulatory mechanisms, this opinion highlights the intricate interplay of histone modifications in preserving transcriptional fidelity and suggests potential pathways for future research to develop novel therapies for age-related disorders and other diseases associated with dysregulated gene expression.

Hong-Yeoul Ryu

Histone Modification Pathways Suppressing Cryptic Transcription

抑制隐蔽转录的组蛋白修饰通路

短名	Epigenomes
Journal Impact	2.56
国际分区	GENETICS & HEREDITY(Q3)

ISSN	2075-4655
h-index	14

涉及主题	生物化学遗传学生物化学基因基因表达表观遗传学DNADNA甲基化医学内科学甲基化细胞生物学组蛋白计算生物学染色质转录因子癌症研究
出版信息	出版商: Multidisciplinary Digital Publishing Institute (MDPI)，出版周期: ，期刊类型: journal，开源期刊: 是
基本数据	创刊年份: 2017，原创研究文献占比: 48.65%，自引率:0.00%， Gold OA占比: 100.00%
期刊费用	$详情
平均审稿周期	网友分享经验：11 Weeks

Epigenomes

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Graft-Derived Cell-Free DNA Quantification following Liver Transplantation Using Tissue-Specific DNA Methylation and Donor-Specific Genotyping Techniques: An Orthogonal Comparison Study

Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV

DNA Imprinting and Differentially Expressed Genes in Longissimus thoracis Muscle of Bos indicus Submitted to Early Weaning Management

Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins

Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins

Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV

DNA Imprinting and Differentially Expressed Genes in Longissimus thoracis Muscle of Bos indicus Submitted to Early Weaning Management

Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins

Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins

Histone Modification Pathways Suppressing Cryptic Transcription