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A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation

ABSTRACT: DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe herein, the development of a 5hmC tissue map by characterizing 5hmC genomic distributions in 19 human tissues derived from 10 organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separated donor samples by tissue type. Further comparison of 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC was preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, we report herein an extensive 5hmC map across diverse human tissue types and suggest an important role of 5hmC in tissue-specific development by integration with public epigenomic data. This resource will facilitate future studies of DNA demethylation in pathogenesis and development of 5hmC as biomarkers for various human diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144530 | GEO | 2020/10/28

REPOSITORIES: GEO

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Whole-genome analysis of 5-hydroxymethylcytosines and 5-methylcytosines at base resolution in human brain

Project description:5-hydroxymethylcytosines (5hmC) is particularly abundant in mammalian brain with little-known functions. Here we present the first genome-wide and single-base-resolution maps of 5hmC and 5mC in human brain by combined application of TAB-Seq and MethylC-Seq. We report that the majority of modified cytosines are hydroxymethylated in adult human brain, a significant proportion of which are highly-hydroxymethylated with enrichment in active genic regions and distal-regulatory elements. 5hmC is more enriched in poised than active enhancers, and CpG island shores and enhancers show comparable 5hmC profiles. Notably, 5hmC spikes were identified at the 5’ splicing sites, suggesting a link between 5hmC and splicing. Additionally, we identified a transcription-correlated 5hmC bias towards to sense strand and a 5mC bias towards antisense strand of gene bodies, and a bias towards C-rich sequences surrounding the 5hmC sites. Our data imply multiple roles for 5hmC in alternative splicing and gene regulation in addition to be an intermediate of DNA demethylation in human brain. Examination of hydroxymethylomes of 1 adult and 1 fetal brain tissue of frontal lobe, as well as 1 methylome of the same adult.

2014-02-14 | E-GEOD-46710 | biostudies-arrayexpress

A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation

Project description:A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation

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DNA 5-hydroxymethylcytosines from cell-free circulating DNA as diagnostic biomarkers for human cancers

Project description:DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-specific epigenetic signatures in cfDNA were identified in different cancers. 5hmC-based biomarkers demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to epigenetic biomarkers from tissue biopsies. This new strategy could lead to the development of an effective blood-based, minimally-invasive cancer diagnosis and prognosis approach.

2017-09-05 | GSE89570 | GEO

Single-step deamination sequencing of 5-hydroxymethylcytosine in genomic DNA at single-base resolution

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Whole-genome analysis of 5-hydroxymethylcytosines and 5-methylcytosines at base resolution in human brain

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Genome-wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes and Alzheimer’s Disease

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2023-05-16 | GSE203337 | GEO

Tissue-specific 5-hydroxymethylcytosine landscape of the human genome

Project description:5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.

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2014-08-01 | E-GEOD-59993 | biostudies-arrayexpress

5-Hydroxymethylcytosines in Circulating Cell-free DNA Reveal Vascular Complications of Type 2 Diabetes

Project description:BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, non-invasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without (testing set: AUC = 0.85, 95%CI, 0.73-0.96), outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84, 95%CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, non-invasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.

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2019-11-15 | GSE126676 | GEO

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