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Gene body DNA hydroxymethylation restricts magnitude of transcriptional changes during aging [direct RNA-seq]

ABSTRACT: DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

ORGANISM(S): Mus musculus

PROVIDER: GSE221122 | GEO | 2023/08/08

REPOSITORIES: GEO

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Gene body DNA hydroxymethylation restricts magnitude of transcriptional changes during aging [hMeDIP]

Project description:DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

2023-08-08 | GSE221121 | GEO

Gene body DNA hydroxymethylation restricts magnitude of transcriptional changes during aging.

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Gene body DNA hydroxymethylation restricts magnitude of transcriptional changes during aging [RNA-seq]

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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

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

2014-02-14 | GSE46710 | GEO

The developmental patterning of 5-hydroxymethylcytosine during neuronal differentiation

Project description:Recent analyses of 5-hydroxymethylcytosine (5hmC) suggest that the modified base influences transcription by acting as an intermediate to demethylation. However, elevated levels of 5hmC within neural tissues suggest that the mark is stable and may directly contribute to gene regulation. Here, we characterize the in vivo genomic patterning and stability of 5hmC in three defined developmental states of the mouse main olfactory epithelium – multipotent stem cells, neuronal progenitors, and mature olfactory sensory neurons. 5hmC is globally enriched in neuronal progenitors and neurons relative to the stem population with significant enrichment on the bodies of transcriptionally active genes and intergenic enhancers. Although gene body 5hmC levels are positively correlated with cell type-specific gene expression in all developmental stages, genes that are commonly expressed within both neuronal progenitors and mature neurons experience the greatest increases in 5hmC levels. Moreover, enriched levels of the modified base on intergenic conserved regions correlate with cell type-specific expression of nearby genes and coincide with developmentally regulated enhancer-promoter interaction at one locus examined. Finally, an analysis of two-month old neurons indicates that elevated 5hmC levels persist in fully differentiated neurons. Together, these data suggest that 5hmC stabilizes the expression of developmentally active genes through effects at both gene bodies and intergenic regulatory elements. 9 Samples

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Analysis of Genome-wide 5-Hydroxymethylation of Blood Samples Stored in Differing Anticoagulants: Opportunities for the Expansion of Clinical Resources for Epigenetic Research

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2023-11-14 | GSE230027 | GEO

Highly-sensitive DNA hydroxymethylation analysis to aid clinic evaluation of myelodysplastic syndromes (MDS)

Project description:Aberrant DNA hydroxymethylation (5hmC) has been reported in patients with myelodysplastic syndromes (MDS). The dysregulation of 5hmC is not only observed in patients with TET2 mutations, but also those bearing other genetic defects, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the status of MDS. To further evaluate the function of 5hmC during MDS pathogenesis, we reported herein an improved highthroughput 5hmC analysis method based on CMS-IP using low input DNA (10 ng) purified from bone marrow aspirates of MDS patients. Our analysis revealed relatively higher heterogeneity of 5hmC signals in MDS patients compared with those of healthy donors, CMML and AML patients. Our systematic bioinformatic analysis further unveiled that 5hmC signatures could be used to separate patients with good and poor clinical outcomes. At the molecular level, we observed dynamic changes of 5hmC within several key transcription factor binding motifs that are essential for hemopoiesis and myeloid lineage specification, which might result in impaired transcriptional outputs during leukemogenesis. Interestingly, we also observed massive changes in 5hmC and transcriptomes in patient showing response to hypomethylating agents (HMA) treatment, suggesting the prognostic value of 5hmC in evaluating epigenetic therapy. Overall, our high-sensitive 5hmC analysis method provides a useful means to greatly facilitate the clinic evaluation for MDS.

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

Project description: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.

2020-10-28 | GSE144530 | GEO

Distinct roles of Tet1 and Tet2 in mouse embryonic stem cells (CMS-Seq)

Project description:The TET proteins TET1, TET2 and TET3 constitute a new family of dioxygenases that utilize molecular oxygen and the cofactors Fe(II) and 2-oxoglutarate to convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and further oxidation products in DNA1-5. Here we show that Tet1 and Tet2 have distinct roles in regulating 5hmC deposition and gene expression in mouse embryonic stem cells (mESC). Tet1 depletion in mESC primarily diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is mostly associated with decreased 5hmC in gene bodies relative to TSS. 5hmC is enriched at exon start and end sites, especially in exons that are highly expressed, and is significantly decreased upon Tet2 knockdown at the boundaries of high-expressed exons that are selectively regulated by Tet2. In differentiating murine B cells, Tet2 deficiency is associated with selective exon exclusion in the gene encoding the transmembrane phosphatase CD45. Tet2 depletion is associated with increased 5hmC and decreased 5mC at promoters/ TSS regions, possibly because of the redundant activity of Tet1. Together, these data indicate a complex interplay between Tet1 and Tet2 in mESC, and show that loss-of-function of a single TET protein does not necessarily lead to loss of 5hmC and a corresponding gain of 5mC, as generally assumed. The relation between Tet2 loss-of-function and selective changes in exon expression could potentially explain the frequent occurrence of both TET2 loss-of-function mutations and mutations in proteins involved in pre-mRNA splicing in myeloid malignancies in humans. Gene and exon expression analysis in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by RNA-sequencing. Mapping of 5-hydroxymethylcytosine in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by anti-CMS-seq. Mapping of methylcytosine in mESC, and Tet2 kd mESC by MeDIP-seq.

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