Identifying and validating molecular targets of interventions that extend the human health span and lifespan has been difficult, as most clinical biomarkers are not sufficiently representative of the fundamental mechanisms of ageing to serve as their indicators. In a recent breakthrough, biomarkers of ageing based on DNA methylation data have enabled accurate age estimates for any tissue across the entire life course. These ‘epigenetic clocks’ link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course. Epigenetic biomarkers may help to address long-standing questions in many fields, including the central question: why do we age?

DNA methylation-based biomarkers and the epigenetic clock theory of ageing

https://hsrc.himmelfarb.gwu.edu/cgi/viewcontent.cgi?article=1037&context=smhs_biochem_facpubs

Histone recognition and large-scale structural analysis of the human bromodomain family.

DNA methylation is of paramount importance for mammalian embryonic development. DNA methylation has numerous functions: it is implicated in the repression of transposons and genes, but is also associated with actively transcribed gene bodies and, in some cases, with gene activation per se. In recent years, sensitive technologies have been developed that allow the interrogation of DNA methylation patterns from a small number of cells. The use of these technologies has greatly improved our knowledge of DNA methylation dynamics and heterogeneity in embryos and in specific tissues. Combined with genetic analyses, it is increasingly apparent that regulation of DNA methylation erasure and (re-)establishment varies considerably between different developmental stages. In this Review, we discuss the mechanisms and functions of DNA methylation and demethylation in both mice and humans at CpG-rich promoters, gene bodies and transposable elements. We highlight the dynamic erasure and re-establishment of DNA methylation in embryonic, germline and somatic cell development. Finally, we provide insights into DNA methylation gained from studying genetic diseases. DNA methylation is essential for mammalian embryogenesis owing to its repression of transposons and genes, but it is also associated with gene activation. The recent use of sensitive technologies has revealed that DNA methylation dynamics vary considerably between embryonic, germline and somatic cell development, with implications for genetic diseases and cancer.

The diverse roles of DNA methylation in mammalian development and disease

A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.

TET-mediated active DNA demethylation: mechanism, function and beyond

DNA methylation is a conserved epigenetic modification that is important for gene regulation and genome stability. Aberrant patterns of DNA methylation can lead to plant developmental abnormalities. A specific DNA methylation state is an outcome of dynamic regulation by de novo methylation, maintenance of methylation and active demethylation, which are catalysed by various enzymes that are targeted by distinct regulatory pathways. In this Review, we discuss DNA methylation in plants, including methylating and demethylating enzymes and regulatory factors, and the coordination of methylation and demethylation activities by a so-called methylstat mechanism; the functions of DNA methylation in regulating transposon silencing, gene expression and chromosome interactions; the roles of DNA methylation in plant development; and the involvement of DNA methylation in plant responses to biotic and abiotic stress conditions.

Dynamics and function of DNA methylation in plants.

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.

/pdf/intragenic-dna-methylation-prevents-spurious-transcription-2vkq2w2fp8.pdf

Intragenic DNA methylation prevents spurious transcription initiation

Histone Crosstalk between H3S10ph and H4K16ac Generates a Histone Code that Mediates Transcription Elongation

Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.

/pdf/tet1-is-a-tumour-suppressor-that-inhibits-colon-cancer-bnxqt4pp4n.pdf

TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway.

https://iris.unito.it/bitstream/2318/141912/1/cell7105_proofs.pdf

Dnmt3L Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in ESCs

Background
Ten-Eleven Translocation (TETs)proteins mediate the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 is expressed at high levels in mouse embryonic stem cells (ESCs), where it mediates the induction of 5hmC decoration on gene-regulatory elements. While the function of Tet1 is known, the mechanisms of its specificity remain unclear.

/pdf/genome-wide-analysis-identifies-a-functional-association-of-xiayytlfd1.pdf

Anna Krepelova

Papers

Intragenic DNA methylation prevents spurious transcription initiation

Histone Crosstalk between H3S10ph and H4K16ac Generates a Histone Code that Mediates Transcription Elongation

TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway.

Dnmt3L Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in ESCs

Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells