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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 the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.

SUBMITTER: Cui XL

PROVIDER: S-EPMC7710742 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Cui Xiao-Long XL Nie Ji J Ku Jeremy J Dougherty Urszula U West-Szymanski Diana C DC Collin Francois F Ellison Christopher K CK Sieh Laura L Ning Yuhong Y Deng Zifeng Z Zhao Carolyn W T CWT Bergamaschi Anna A Pekow Joel J Wei Jiangbo J Beadell Alana V AV Zhang Zhou Z Sharma Geeta G Talwar Raman R Arensdorf Patrick P Karpus Jason J Goel Ajay A Bissonnette Marc M Zhang Wei W Levy Samuel S He Chuan C

Nature communications 20201202 1

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 the development of a 5hmC tissue map by c ...[more]

PMID: 33268789

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Project description:The genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.

Project description:The transcription activity of the tumor-specific promoter may be increased using specific DNA sequences such as simian virus 40 (SV40). Human heparanase (HPSE) gene promoter is also considered a tumor-specific promoter. However, whether or not the SV40 enhancer affects the tumor specificity of HPSE remains to be determined. The SV40 enhancer sequence, 237 bp in length, was amplified and correctly inserted into the assigned multiple clone sites (MCS) of the eukaryotic expression vector pEGFP-Hp, which was constructed in advance. The recombinant plasmid pEGFP-Hp-SV40e was consistent with the anticipated Genbank data and transfected into human umbilical vein endothelial cell (ECV) and tumor cell lines, including hepatoma carcinoma (HepG2), laryngeal carcinoma (Hep2) and chronic myelogenous leukemia cell lines (K562) using lipofectamine, respectively. The expression of the reporter gene, green fluorescent protein (GFP), was detected using fluorescence microscopy and flow cytometry. The length of the amplified SV40 enchancer was 237 bp and the sequence was in accordance with the GenBank data. The recombinant plasmid pEGFP-Hp-SV40 was consistent with the anticipated results. Fluorimetric analysis showed that the fluorescence of pEGFP-Hp-SV40e in ECV cells was as dim as pEGFP-Hp, and obviously weaker than pEGFPN1. In tumor cells including HepG2, Hep2 and K562 cells, the fluorescence of pEGFP-Hp-SV40e was similar to that of pEGFP-N1, which was clearly brighter than pEGFP-Hp. The average transfecion rates in the 4 types of cells were 4.1, 17.2, 8.8 and 6.4% in the pEGFP-Hp; 18.3, 29.3, 17.0 and 13.0% in the pEGFP-Nl and 4.3, 28.8, 16.4 and 11.7% in the pEGFP-Hp-SV40e groups, respectively. The ratio of pEGFP-Hp-SV40e to pEGFP-Hp in all cells was 1.05, 1.67, 1.86 and 1.83, respectively. In conclusion, the inserted SV40 enhancer sequence is able to improve the transcriptional activity of the human HPSE gene promoter, but does not affect its tumor specificity.

Dataset Information

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

Publications

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

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