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Identification of genes implicated in epigenetic age
DNA methylation changes over time, reflecting the age of an individual. CpG DNA methylation levels can give a measure of epigenetic age of a tissue, a factor that has been shown to correlate with mortality; for example, the epigenetic age of blood has been found to be associated with all-cause mortality.
In this paper, a team led by Steve Horvath from the University of California, Los Angeles investigated whether cerebellar epigenetic age acceleration – DNA methylation age adjusted for chronological age – could be used as an endophenotype for biological age. Using a genome-wide association study, they found the following:
This is the first paper that presents SNPs associated with epigenetic age acceleration and shows correlation with expression of an implicated gene. By doing this, the authors have shown the utility of using epigenetic tissue age as an endophenotype, rather than linking SNPs directly to clinical outcomes.
Read the full paper at Nature Communications, February 2016.
5-hmC and TET are required for DNA repair
During DNA demethylation, ten-eleven translocation (TET) enzymes convert 5-methylcytosine (5-mC) to 5-hydroxylmethylcytosine (5-hmC). Epigenetic 5-hmC DNA modification impacts gene expression and 5-hmC-containing regions have a more open chromatin confirmation.
Upon DNA damage, cells attempt to repair DNA by the DNA damage response (DDR) pathway. This mechanism is dependent of the relaxation of chromatin to allow access for protein complexes. In this paper, a team led by Peter Mark Carlton form Kyoto University in Japan aimed to find out how 5-hmC contributes to the DDR.
The results presented in this paper show that 5-hmC and TET enzymes are essential for DNA repair and genome integrity.
Read the full paper in Cell Reports, February 2016.
Telomere chromatin compaction reduces accessibility to DNA damage response components
Chromosome ends are often misrecognized as DNA breaks. The shelterin protein complex protects telomeres from the DNA repair mechanism. Dysregulation of this process is implicated in cancer and aging; however, it is not clear how shelterin exerts its protective function.
To find out how shelterin protects telomere ends, a team led by Ahmet Yildiz from the University of California, Berkeley investigated the structure of telomeric chromatin using super-resolution microscopy on human cells.
The results presented in this paper suggest that shelterin-mediated telomere compaction reduce telomere-dysfunction-induced loci and protects chromosome ends from the DDR machinery.
Read the full paper in Cell, February 2016.
H2A.X regulates the epithelial-mesenchymal transition
For cancer cells to spread throughout the body by metastasis, they must undergo epithelial-mesenchymal transition (EMT). EMT-related transcription factors are regulated by changes to chromatin configuration, and there is evidence that loss of the histone variant H2A.X results in increased cell migration and invasion.
To further understand mechanisms regulating the EMT, a team led by William Bonner from the National Cancer Institute, Maryland investigated whether H2A.X downregulation induces changes in cancer gene expression that result in EMT. Using human colon carcinoma cell lines, they found the following:
The results presented in this paper demonstrate that restoration of H2A.X expression results in partial EMT reversal, that is necessary for metastasis. These results suggest that H2A.X is a regulator of EMT.
Read the full paper in Nature Communications, February 2016.
Regulation of stem cell phenotype by DNA methylation, miRNAs and HMGA1
Multipotent cancer stem cells are important contributors to tumor growth, therapeutic resistance and recurrence. The extreme plasticity of these cells means that epigenetic modification of gene networks allows them to move between a stem-like state that propagates tumor growth and more differentiated non-tumor-propagating states.
A team led by John Laterra from the John Hopkins School of Medicine in Maryland sought to understand how cross-talk between DNA methylation, miRNA expression and transcription factors regulate stem cells in glioblastoma. They found the following:
This work uncovers how an interaction between DNA methylation, miRNAs and HMGA1 regulation of SOX2 contributes to stem cell phenotype. The authors suggest that miR-269-5p might be a potential therapeutic tool to inhibit stem cell populations in glioblastoma.
Read the full paper in Oncogene, February 2016.
Two-step process for MLL activation
Mixed lineage leukemia (MLL) proteins methylate histone H3 at lysine 4 (H3K4). MLL1 protein on its own has poor methyltransferase activity; its activity is enhanced by additional factors including WDR5, RBBP5 and ASH2L. However, how these factors act to regulate MLL1 activity is still unsolved.
To understand this further, a team led by Ming Lei from the Chinese Academy of Sciences used structural, biochemical and computational analyses to look at the structure of MLL proteins in complex with WDR5, RBBP5 and ASHL2. They found the following:
The authors have shown that a two-step process occurs for MLL activation composed of stabilization of the MLL SET domain by RBBP5-ASH2L binding, followed by further activation by binding to the H3 substrate itself.
Read the full paper in Nature, February 2016.
A new methods for studying DNA methylation in non-model species
DNA methylation is analyzed by bisulfite sequencing, in which unmethylated cytosines are converted to uracil. Currently available reduced representation bisulfite sequencing (RRBS) methods are limiting in terms of enzyme selection and multiplex ability, and are dependent on availability of a reference genome.
In this paper, a team led by Koen Verhoeven from the Netherlands Institute of Ecology present epiGBS – a method that enables reference-free RRBS of highly multiplexed libraries by extending genotying by sequencing (GBS) with bisulfite treatment. Here is what the technique involves:
This method will be useful for examining DNA methylation in non-model organisms for which a reference genome is not available.
Read the full paper in Nature Methods, February 2016.