The Multiple Roles of ATRX
ATRX is a SWI/SNF-like chromatin remodeler that has been implicated in transcriptional regulation through multiple mechanisms, including via the regulation of histone variant deposition. Mutations in ATRX were first identified in patients bearing the syndrome after which the gene is named, α thalassemia/mental retardation X-linked. In addition, ATRX is mutated at high percentages in multiple tumor types, which suggests a potential ‘driver’ role in cancer. In this issue of Epigenetics, Ratnakumar and Bernstein discuss the multiple roles for ATRX in transcriptional regulation and histone deposition.
Set2, Chromatin Structure and Transcription Elongation
The maintenance of an ordered chromatin structure over the body of genes is vital for the regulation of transcription. Smolle et al. review two recent papers that show how the Set2-mediated methylation of H3K36 maintains chromatin structure by limiting histone dynamics over gene bodies, either by recruiting chromatin remodelers that preserve ordered nucleosomal distribution or by lowering the binding affinity of histone chaperones for histones, preventing their removal.
G9a: A Multipotent Regulator of Gene Expression
G9a is a methyltransferase mostly associated with transcriptional repression. However, recent studies have highlighted its role as an activator of gene expression through mechanisms that are independent of its methyltransferase activity. In this issue of Epigenetics, Shankar et al. review the different molecular mechanisms and substrates through which G9a regulates gene expression. The authors also discuss emerging evidence for its wide-ranging functions in development, pluripotency, cellular differentiation and cell cycle regulation, which underscore the complexity of its functions. The deregulated expression of G9a in cancers and other human pathologies suggests that it may be a viable therapeutic target in various diseases.
Socioeconomic Factors and DNA Methylation
Epigenetic modifications may be one mechanism linking early life factors, including parental socioeconomic status (SES), to adult onset disease risk. Tehranifar et al. studied the influence of SES on DNA methylation patterns in a US birth cohort of women, examining whether indicators of early life and adult SES were associated with white blood cell methylation of repetitive elements in adulthood.
Premature Aging Disorders and DNA Methylation
DNA methylation changes with age and is likely to play a role in aging-related processes. Two premature diseases, Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS), show features of common natural aging early in life. In a subset of patients, mutation in the LMNA and WRN genes has been associated to disease onset. Heyn et al. have now studied the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. The authors observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients. Interestingly, non-mutant patients revealed differential DNA methylation at distinct loci. The authors propose that DNA methylation has an impact on premature aging diseases.
Genome-Wide DNA Methylation in HCC
In this issue of Epigenetics, Shen et al. have used Infinium HumanMethylation 450K BeadChip arrays to study DNA methylation patterns in hepatocellular carcinoma (HCC). In tumor tissues from HCC cases, the authors identified aberrant DNA methylation profiles across the genome, which were predominantly related to HCV infection. Their extensive results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.
Homocysteine Metabolism and H19/Igf2 Imprinting
DNA methylation is linked to homocysteine metabolism through the generation of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy). The ratio of AdoMet/AdoHcy is often considered an indicator of tissue methylation capacity. Glier et al. have now studied the relationship between tissue concentrations of AdoMet and AdoHcy and the allele-specific methylation and expression of genomically imprinted H19/Igf2 in mice. Their interesting findings suggest that the relationship between the AdoMet/AdoHcy ratio and gene-specific DNA methylation is tissue-specific and that changes in H19/Igf2 methylation can occur without changes in AdoMet and AdoHcy.
Honokiol Inhibition of Class I HDAC in NSCLC
In this issue, Singh et al. report on the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on non-small-cell lung cancer (NSCLC) cells. The author used in vitro and in vivo models to study the molecular mechanisms underlying the effects of honokiol.
Treatment of NSCLC cells with honokiol inhibited HDAC activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects were associated with a significant reduction in the viability of NSCLC cells. Oral administration of honokiol significantly inhibited the growth of subcutaneous tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. This study provides new insights into the role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells.
Epigenetic Regulation of NKG2D in CD8+ T and NK cells
The human activating receptor NKG2D is mainly expressed by NK, NKT, γδ T and CD8+ T cells and, under certain conditions, by CD4+ T cells. This receptor recognizes a diverse family of ligands, leading to the activation of effector cells and triggering the lysis of target cells. The NKG2D receptor-ligand system plays an important role in the immune response to infections, tumors, transplanted graft and autoantigens. Now, Fernández-Sánchez et al. investigated the role of epigenetic mechanisms in NKG2D gene regulation in T lymphocytes and NK cells. Their findings suggest that differential NKG2D expression in the different cell subsets is regulated by epigenetic mechanisms and that its modulation by epigenetic treatments might provide a new strategy for treating several pathologies.
Chromatin Regulation in Planarian Stem Cells
In this issue of Epigenetics, the role of chromatin regulation in stem cells was studied in vivo by looking at regeneration in the freshwater planarian Schmidtea mediterranea. These animals possess a high concentration of pluripotent stem cells, which are capable of restoring any damaged or lost tissues after injury or amputation. Hubert et al. identified S. mediterranea homologs of the SET1/MLL family of histone methyltransferases and COMPASS and COMPASS-like complex proteins and investigated their role in stem cell function during regeneration. With this work, the authors characterized the function of the SET1/MLL family in the context of planarian regeneration and provided insight into the role of these enzymes in adult stem cell regulation in vivo.
The Epigenome of AML Stem and Progenitor Cells
Acute myeloid leukemia (AML) is sustained by a population of cancer stem cells (CSCs); however, the mechanisms underlying switches from CSCs to non-CSCs in vivo are not understood. Yamazaki et al. performed a genome-wide screening for DNA methylation and selected histone modifications. The authors found no major differences in DNA methylation, especially in promoter CpG islands, between CSCs and non-CSCs. By contrast, they found thousands of genes that change H3K4me3 and/or H3K27me3 status between stem and progenitor cells as well as between progenitor and mature cells. This novel data indicates that histone modifications, but not promoter DNA methylation, are involved in switches from CSCs to non-CSCs in AML.
Breast Cancer and keap1 Methylation
Keap1 is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. In this issue, Barbano et al. determined the methylation status of the KEAP1 promoter in primary breast cancers, pre-invasive lesions and paired normal breast tissues by quantitative methylation specific PCR. Among their results, the authors found that aberrant promoter methylation of the KEAP1 gene is involved in breast cancerogenesis. The identification of patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.
SuBLiME: A New Method for the Enrichment of Methylated DNA
Ross et al. describe a new method, called streptavidin bisulfite ligand methylation enrichment (SuBLiME), that involves the specific labeling (using a biotin-labeled nucleotide ligand) of methylated cytosines in bisulfite-converted DNA. The authors argue that SuBLiME is highly adaptable and can be combined with deep sequencing library generation and/or genomic complexity-reduction. SuBLiME is effective in the enrichment of methylated nucleic acid and in the detection of known and novel biomarkers. Here, the authors used SuBLiME in a pilot study aimed at the discovery of colorectal cancer biomarkers from leukocytes.