Epigenetic News

Novel Histone Modifying Enzyme Associated with Cancer
Researchers in Spain have discovered a novel histone-modifying activity associated with the regulation of gene expression. Working at IMIM-Hospital del Mar in Barcelona, the group identified a histone-modifying activity in the LOXL2 (Lysyl oxidase-like 2) protein. Rather than adding or subtracting a specific mark, the LOXL2 enzyme cleaves off the amino side chain on histone H3 at lysine 4, particularly when that amino side chain is trimethylated. As H3K4me3 is associated with genes that are actively transcribed, the deaminating activity of LOXL2 suggests that it is a repressor of gene expression. Indeed, knockdown of LOXL2 stimulated the expression of the CDH1 gene, indicating that LOXL2 is involved in the repression of CDH1. LOXL2 expression is high in a number of cancers, and previous studies in which LOXL2 lysine oxidase activity was inhibited led to a reduction in breast cancer cell metastasis. These data and the new activity identified for LOXL2 suggest that it would make a good target for cancer drug development.
Herranz et al. (2012) Mol Cell Apr 5, Epub ahead of print.
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New Technique Enables Direct Sequencing of 5-hydroxymethylcytosine
There are many forms of DNA methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC), and their similarities have made it difficult to discriminate between them, until now. Researchers at the University of Cambridge and the Babraham Institute have developed a technique that enables single-base resolution of both 5-mC and 5-hmC. The new technique, termed oxBS-Seq, involves selective chemical oxidation of 5-hmC, followed by bisulfite sequencing, which converts 5-hmC into uracil. “There was a real need in the field for a technique that would map both 5hmC and 5mC in the genome quantitatively and at high resolution,” states joint lead author Dr. Miguel Branco. This technique should facilitate the understanding of 5-hmC function in many areas, including embryonic development and stem cell biology.
Booth et al. (2012) Science Apr 26, Epub ahead of print.
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Deubiquitinase Shown to Suppress a Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA) is an aggressive form of cancer with a very high rate of mortality. To search for tumor suppressors that are inactivated in PDA, researchers in the UK, USA, Germany and Australia used a transposon-mediated approach in mice and identified the Usp9x gene, which encodes a ubiquitin protease. Knockdown of Usp9x in mice promotes tumorigenesis. Usp9x was found to protect cancer cells from programmed cell death. Reduced expression of the human homologue, USP9X, is correlated with shortened survival in one prostate cancer study. USP9X appears to be epigenetically silenced as its expression is upregulated in human cancer cell lines with the addition of the HDAC inhibitor trichostatin or the DNA methylation inhibitor decitabine (5-aza-2′-deoxycytidine). These data suggest a potential treatment for PDA patients in order to restore USP9X levels, which could slow progression of the disease.
Pérez-Mancera et al. (2012) Nature Apr 29, Epub ahead of print.
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High Resolution Maps of DNA Methylation in Early Mammalian Embryos
DNA methylation during development is an extremely dynamic process, and a recent study from several research groups in Boston has led to the generation of genome-wide maps of the early mammalian embryo. Working at the Broad Institute, Harvard and MIT, researchers created reduced representation bisulfite sequencing (RRBS) libraries from mouse oocytes and sperm, as well as from zygote to post-implantation embryos. It was determined that the oocyte is already hypomethylated prior to fertilization, and has a pattern of methylation much like the early embryo. Thus it seems that the pattern of embryonic methylation is dictated primarily by the oocyte. Two major transitions in methylation were observed: from sperm to zygote, and from inner cell mass to post-implantation embryo. After fertilization, sperm chromatin was dramatically demethylated; following implantation, the embryo exhibited whole-scale remethylation. Many differentially methylated regions (DMRs) were found to persist throughout early embryogenesis, but the locations differ depending on the gamete source. DMRs from oocytes are primarily promoter-associated, whereas the sperm-derived DMRs are largely intergenic. This new study is a dramatic improvement over previous studies that measured global levels of methylation across the genome.
Smith et al. (2012) Nature 484(7394):339-344.
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Reprogramming of Cancer Cells Achieved with Low Doses of DNA Demethylating Drugs
The DNA demethylating agents azacytidine (AZA) and decitabine (DAC) are extremely toxic to normal cells at the high doses required to kill cancer cells, and thus are no longer in use for treating cancer. Cancer researchers in Maryland, Utah and Belgium have found that these drugs can still be useful when used at lower doses, well below the levels that are harmful to cells. The researchers took the approach to transiently expose metastatic breast cancer cells in culture to the drugs and then transplant them into mice. In most cases, the cancer cells adopted a more normal cell fate and eventually died. Rather than killing the rapidly dividing cells, this approach appears to have reprogrammed cells through widespread promoter demethylation, activating silenced genes that regulate cell cycle progression, differentiation and programmed cell death. This phenomenon, an anti-tumor “memory” effect, also seemed to inhibit the growth of sub-populations of cancer cells with stem cell-like properties. This study explains results of clinical trials with the drugs where patients continued to experience the anti-cancer effects of the drugs long after administration was halted. Low dose therapy using these drugs is already approved by the FDA for treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), so clinical trials for other cancers employing low dose AZA and DAC should be underway quickly.
Tsai et al. (2012) Cancer Cell 21(3):430-446.
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Shortened Telomeres Associated with Increased Risk of Heart Disease
It is well established that telomeres, the protective protein/DNA complexes that are present at the ends of chromosomes, gradually shorten with age. However, increased age only accounts for a percentage of telomere length variability. Other factors, such as smoking, also contribute to the shortening of telomeres. A recent study undertaken at Brigham and Women’s Hospital correlates reduced telomere length with increased risk of heart attack or death from cardiovascular failure. The study followed 5,044 cardiology patients for 18 months and found that patients with the shortest telomeres were at the greatest risk for suffering a severe coronary or cardiovascular event, many leading to death. “Even when accounting for all of these other known risk factors, patients with short telomeres have an increased risk of having a heart attack or dying from heart disease,” states lead investigator Christian Ruff, MD. It is possible that measuring telomere length might aid cardiologists in establishing the prognosis for their patients.
Presented at the American College of Cardiology 2012 Annual Scientific Session in Chicago, IL (March 24-26, 2012).
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Chromatin Basis for Pediatric Brain Cancer Uncovered
Brain tumors are the most common cause of cancer-related mortality in children. Using high-throughput DNA sequencing, researchers working in Canada and Germany have uncovered a connection between pediatric glioblastoma multiforme (GBM) and chromatin structure. They identified many mutations in genes in the DAXX-ATRX histone chaperone pathway. ATRX and DAXX serve to incorporate the histone variant H3.3 at telomeres, and mutations in ATRX, DAXX and H3.3 were found at high frequency in pediatric GBM tumor samples. Frequent mutations in the p53 gene were also observed. These mutations were not found in samples from adult GBM patients, indicating that this might explain the differences between adult and pediatric GBM. Glioblastoma multiforme in children is particularly aggressive and almost always fatal. Says McGill University professor and pediatric hematologist-oncologist specialist Dr. Nada Jabado, “It is clear now that glioblastoma in children is due to different molecular mechanisms than those in adults, and should not be treated in the same way.” Hopefully this new information will lead to more effective therapeutic regimes for pediatric GBM.
Schwartzentruber et al. (2012) Nature Jan 29, Epub ahead of print.
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A Potential Epigenetic Cause for Alzheimer’s Disease
A group of researchers working at MIT, Harvard and Boston University have uncovered an epigenetic connection to Alzheimer’s that may lead to a new treatment for the disease. Previous studies suggested that Alzheimer’s may be associated with decreased levels of histone acetylation. The Boston group discovered that a particular enzyme regulating levels of histone acetylation, HDAC2, is expressed more highly in Alzheimer’s patients and in mouse models of the disease. When expression of HDAC2 was blocked in the Alzheimer’s mouse model, significant increases in synapse density were observed. It was also observed that oxidative stress and amyloid beta protein can activate expression of glucocorticoid receptor, which then turns on HDAC2 at high levels. HDAC2 was found to bind to a number of genes involved in learning and memory, reducing their expression. Clinical trials targeting HDAC2 for the treatment of Alzheimer’s disease are already in the works.
Gräff et al. (2012) Nature Feb 29, Epub ahead of print.
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DNA Methylation Patterns in Brain Correlated with Age
Researchers at the National Institute of Mental Health (NIMH) measured DNA methylation in brain using samples derived from the pre-frontal cortex that ranged in age from fetal to elderly. CpG methylation was examined at promoters associated with 14,500 genes. Methylation became more frequent at sites with increased age, and at specific classes of genes, and correlated with decreases in gene expression. This study will help shed light on a variety of mental disorders with no defined genetic basis, including schizophrenia, autism and bipolar disorder, and how changes in the environment can influence behavior.
Numata et al. (2012) Amer J of Hum Gen 90(2):260-272.
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Inactivating Mutations in Polycomb Genes Contribute to Leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that afflicts children primarily. T-cells divide unchecked, due for the most part to unregulated activity of the Notch1 protein. A recent study conducted at the NYU Cancer Institute has shed light on the mechanism of T-ALL development and the role of Notch1. Using mouse models of T-ALL, the researchers found that inappropriately activated Notch1 antagonized Polycomb-mediated repression and abrogated histone H3 Lys27 trimethylation at specific loci. It was also determined that mutations in genes encoding Polycomb proteins Suz12 and EZH2 are found in 25% of patients with T-ALL. Suz12 and EZH2 are members of the Polycomb Repressive Complex 2 (PRC2) responsible for methylation of histone H3 at Lys27, and crucial for establishing repression at specific genes. It is likely that the ablation of PRC2 activity contributes to the development of T-ALL, potentially facilitating the activation by Notch1 of specific genes that are normally repressed in T-cells by the action of the Polycomb proteins. “The inactivation of PRC2 complex due to Notch in T-ALL constitutes an important pathogenetic event in the formation of this potentially deadly disease,” states the paper’s senior author and NYU researcher Panagiotis Ntziachristos.
Ntziachristos et al. (2012) Nature Medicine Jan 11, Epub ahead of print.
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Chromatin Remodeling Factors Directly Linked to 5-hmC Methylation and Regulation of Stem Cell Pluripotency
A recent study examining the role of chromatin remodeling proteins in the maintenance of embryonic stem (ES) cell pluripotency has led to some surprising connections with DNA methylation. The BAF (Brahma/BRG1 Associated Factor) chromatin remodeling complex is crucial for expression of genes involved in pluripotency, whereas the NuRD (Nucleosome Remodeling and Deacetylase) complex works in opposition to BAF. In the study, conducted at the University of Massachusetts Medical School, it was found that both BRG1 (a component of a stem cell-specific BAF complex, esBAF) and MBD3 (a component of NuRD) were found localized to a large number of genes in stem cells. It was also found that MBD3 binds preferentially to 5-hydroxymethylcytosine (5-hmC) methylation, whereas the other MBD family proteins bind to 5-methylcytosine (5-mC) methylation. Both BRG1 and MBD3 are required for normal levels of 5-hmC methylation in the genome. It is known that many master regulatory genes in stem cells exhibit the hallmarks of both active and repressed genes, indicating that they were poised for both states of expression. This study adds further evidence to the model that the antagonistic interplay between activating and repressing factors is crucial to the proper regulation of key stem cell pluripotency genes.
Yildirim et al. (2011) Cell 147(7):1498-1510.
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Chemical Library Screen Leads to a Potential Treatment for Angelman Syndrome
Angelman Syndrome is a neurodevelopmental disorder caused by mutations in the maternally-inherited allele of the UBE3A gene, which encodes a ubiquitin protein ligase. Mutations in or deletions of the maternal allele lead to a complete loss of UBE3A function as the paternal allele is imprinted in neurons, due to the action of an antisense RNA. Using mice that express a fluorescently tagged version of the paternal UBE3A protein (Ube3A-YFP), researchers at the University of North Carolina at Chapel Hill tested a panel of drugs from an NIH small molecule library on primary neurons from the model mice. They determined that several drugs that inhibit topoisomerase function led to re-activation of paternal UBE3A gene expression. Topoisomerases are enzymes that help regulate the structure of DNA. It was further discovered that the topoisomerase inhibitors were unsilencing the UBE3A gene by reducing the expression of the imprinted antisense RNA. Explaining the rationale behind the study, UNC neuroscientist Benjamin Philpot states, “We wanted to determine if there could be a way to ‘awaken’ the dormant (paternal) allele and restore UBE3A expression in neurons.” This discovery holds great promise for the treatment of Angelman syndrome.
Huang et al. (2012) Nature 481(7380):185-189.
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New DNA Modifications in Mouse Zygote Removed by Replicative Dilution
Researchers at the University of North Carolina’s Lineberger Comprehensive Cancer Center recently published results of their study examining the role of two new DNA methylation variants in mouse development. The group, led by Professor Yi Zhang, found that the two new modifications, 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), appear in the paternal pronucleus after fertilization, concomitant with the disappearance of 5-methylcytosine (5-mC). The Zhang lab had previously identified the existence of these novel forms of DNA methylation in embryonic stem cells. The Tet family of cytosine oxygenase enzymes, which convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), further oxidize 5-hmC into 5-fC and 5-caC. The UNC group found that rather than being enzymatically removed, the levels of 5-fC and 5-caC are gradually diluted out by DNA replication. While this pathway represents a mechanism by which DNA methylation (5-mC) is removed, the novel modifications may also be serving some unique function in pre-implantation development.
Inoue et al. (2011) Cell Research 21:1670-1676.
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Epigenetic Mechanism Identified for Temperature Regulated Sex Determination in Fish
Much historical data exists showing the importance of temperature in the determination of sex in fishes and other vertebrates. As the water temperature varies, the ratio of fish that develop as males or females can be altered dramatically, despite the underlying genetics. A group of researchers in Spain studying the European sea bass found that by increasing the temperature during a critical period of development, a population of fish that develop entirely as males can be produced. They identified a gene, aromatase, whose promoter was methylated specifically in the developing gonad as a result of the elevated temperature, thus preventing its expression. The aromatase enzyme converts androgens into estrogens, and silencing of aromatase gene expression at a critical period in gonad development facilitated the sex reversal. Interestingly, this finding explains why fish farms produce higher proportions of male fish, as the farmers elevate water temperature to increase the speed of growth.
Navarro-Martín et al. (2011) PLoS Genetics 7(12):e1002447.
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Transcription Elongation Factors Found Specific to snRNA Genes
Researchers at the Stowers Institute for Medical Research have identified a protein complex involved in transcriptional elongation that appears to be specific for snRNA-encoding genes. It was found that the ELL protein, previously known to be part of the “Super Elongation Complex” (SEC) and involved in elongation of mRNA-encoding genes, was also part of a different elongation complex. The newly identified complex, the “Little Elongation Complex” (LEC) was found to be enriched at genes encoding snRNAs. It was also found that components of the LEC are required for proper levels of snRNA gene expression. This work is the first such example of a class of elongation proteins that are specialized for a particular type of gene and may herald the identification of other similarly specific factors. “The specificity of the complexes seems to control which classes of genes are transcriptionally regulated”, says study leader and lab head Professor Ali Shilatifard.
Smith et al. (2011) Molecular Cell 44(6):654-965.
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Mechanism of Centromere Specification Determined by Epigenetic Inheritance of Histone H3 Variant
The centromere is a specialized region of the eukaryotic chromosome that is essential for cell survival, as it specifies the point of attachment for spindle microtubules during cell division. A recent study conducted in Germany provides new information with regard to how centromere position is determined. In most eukaryotes, the position of the centromere is not dictated by DNA sequence. The group in Germany, working at the Max Planck Institute of Immunobiology in Freiburg, has found that the localization of the centromeric histone H3 variant (CenH3) specifies centromere position. Using the fruitfly Drosophila as a model organism, the researchers found that they could induce formation of a new centromere by targeting the Drosophila CenH3 (a protein called CID) to a different region of the chromosome. The ectopic CID protein was incorporated into chromatin, formed new functional centromeres, specified the deposition of many kinetochore proteins, and established new sites for microtubule attachment. When directed to bind to a region in an extra-chromosomal DNA element, this episome was stably replicated and maintained through dozens of cell divisions, even in the absence of the targeting sequence. Thus it appears that the localization of CenH3 is necessary and sufficient to specify the location of a centromere in Drosophila, raising the question if this is also true in mammals.
Mendiburo et al. (2011) Science 334(6056):686-690.
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Genome Wide Analysis of p53 Binding in Normal Cells Sheds Light on Its Role as Tumor Suppressor
The tumor suppressor protein p53 is one of the most widely studied transcription factors due to its crucial role in maintaining the integrity of DNA and the cell. Researchers at the Brookhaven National Lab have undertaken the first genome-wide analysis study of p53 distribution in normal cells, IMR90 fibroblasts. They have compared the data to other genome-wide studies performed using cancer-derived cell lines, as well as to DNA methylation data from a previous IMR90 study. The researchers found that more than 40% of the p53 binding sites were within 2 kilobases of a transcriptional start site, which had not been observed in previous work using cancer-derived cell lines. Additionally, almost half of the binding sites were found to be within CpG islands and, in general, p53 binding was found in hypomethylated regions, another difference between normal and cancer cells. It is possible that the observed binding of p53 in normal cells is different compared to cancer cells due to changes in chromatin structure and DNA methylation between them, and that these differences limit the availability of p53 binding sites. “This research makes it clear that it is essential to study p53 functions in both types of cells in the context of chromatin to gain a correct understanding of how p53 tumor suppression is affected by global epigenetic changes — modifications to DNA or chromatin — associated with cancer development,” stated lead author Krassimira Botcheva.
Botcheva et al. (2011) Cell Cycle 10(24):4237-4249.
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Single Molecule Sequencing of 5-Hydroxymethylcytosine
The term DNA methylation has expanded recently to include a number of modifications to DNA other than the original 5-methylcytosine (5-mC) methylation. One of these modifications is 5-hydroxymethylcytosine (5-hmC), a form of DNA methylation that is enriched in embryonic stem cells and is functionally distinct from 5-mC methylation. Techniques used to study 5-mC methylation are useless when it comes to 5-hmC methylation, so new methods must be developed. Researchers at The University of Chicago and Pacific Biosciences, a company developing novel methods of sequencing DNA, have recently developed a sensitive method to analyze the distribution of 5-hmC by combining a novel chemical labeling method with single-molecule sequencing. The input DNA is modified such that a cleavable biotin tag is specifically added to the hydroxyl group of 5-hmC, allowing for DNA containing 5-hmC to be enriched. The biotin tag is then removed and the DNA subjected to single-molecule, real time (SMRT) sequencing using the platform developed by Pacific Biosciences. The sequencing reaction for 5-hmC can be discerned from the sequencing of unmethylated or 5-mC methylated DNA, and thus the positions of 5-hmC methylation can be accurately mapped. This new technique should provide researchers with a useful tool in the study of DNA 5-hmC methylation.
Song et al. (2012) Nature Methods 9(1):75-77.
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A Novel Connection Between DNA Methylation and Cancer Identified
Methylation of the C5 of cytosine (5-methylcytosine) is an epigenetic mark regulating genome function, but methylation of the N3 position is potentially mutagenic. Multiple mechanisms exist to repair this type of DNA lesion, and a recent study at Harvard University sheds light on the mechanism of one such repair protein, ALKBH3. ALKBH3 was found to be associated with a protein complex (ASCC) previously implicated in transcriptional activation. One subunit of the ASCC complex, ASCC3, encodes a DNA helicase that creates a region of single-stranded DNA that is required by ALKBH3 to facilitate repair of the methyl adduct. Loss of the ALKBH3 repair activity was found to reduce proliferation of several tumor cell lines in culture, and resulted in impaired tumor formation in mouse xenograft models. It is possible that ALKBH3 or ASCC3 could be targeted for therapeutic intervention in cancer.
Dango et al. (2011) Molecular Cell 44(3):373-384.
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Histone Binding Protein Regulates Gene Activation After Mitosis
During mitosis, chromatin is compacted into a transcriptionally silent state, but after cell division, genes are reactivated to their pre-mitotic pattern in a process termed “gene bookmarking.” A recent study conducted at Cold Spring Harbor Laboratories and the Tokyo Medical and Dental University has uncovered a possible mechanism by which gene bookmarking is achieved. Using a chromosomally integrated and inducible RNA polymerase II-transcribed reporter, the kinetics of gene activation were studied in both interphase and post-mitotic cells. It was determined that post-mitotic induction of gene expression occurred 13 times faster than during interphase. Further study revealed that an increase in histone H4 acetylated at lysine 5 (H4K5Ac) served as an epigenetic bookmark that persisted through mitosis, and that recognition of H4K5Ac by the bromodomain protein BRD4 facilitated the rapid post-mitotic increase in gene activation. It is likely that this mechanism extends to a number of genes activated post-mitosis, and it is possible that different marks, or ‘bookmarks’ exist for different classes of genes.
Zhao et al. (2011) Nature Cell Biology 13(11):1295-1304.
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New Role for Histone Demethylase Identified in Mechanism of Circadian Rhythm Regulation
A study conducted at the Salk Institute into the mechanisms regulating circadian rhythms has identified a new role for the histone demethylase JARID1a. Circadian rhythms, which regulate the ‘sleep-wake’ cycle, involve the daily rise and nightly fall in expression of a key regulator, the Period (Per) protein. JARID1a was found to counteract the activity of HDAC1 at the Per gene promoter, thus allowing expression of the Per gene in the morning to activate the ‘sleep’ part of the ‘sleep-wake’ cycle. However, JARID1a’s activation of Per expression required only its presence at the Per gene promoter, not its activity as a histone demethylase. It is possible that JARID1a may be directly counteracting HDAC1 activity, or possibly recruiting another factor involved in antagonizing HDAC1.
DiTacchio et al. (2011) Science 333(6051):1881-11885.
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