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Epigenetics News

May 2016

DNA methylation on N6-adenine in mammalian embryonic stem cells.
In this recent publication, researchers from Yale University identified a new DNA methylation mark in mammalian embryonic stem cells. To investigate this new mark, researchers applied a targeted ChIP-Seq method focusing on genomic regions enriched in the H2A.X marker. Results indicate that this new mark, N6-methyladenine, is localized at the 5’UTRs and ORFs of LINE-1 retroelements and that enrichment of N6-methyladenine is correlated with the epigenetic silencing and downregulation of neighbouring genes. This study elucidates the importance of a novel DNA modification mark in regulating epigenetic mechanisms related to retrotransposon and gene silencing in early embryonic development.
Wu, T.P. et al. Nature. 21 Apr 2016. DOI: 10.1038/nature17640.
Abstract.

Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters.
Histone lysine butyrylation is a conserved post-translational modification that is correlated with high gene expression. In the current issue of Molecular Cell, researchers investigate the role of butyrylation during mammalian spermatogenesis through a series of in vitro and genome wide analyses. Results indicate that, despite acting as a direct stimulator of transcription, histone butyrylation competes with acetylation, especially at H4 K5, to prevent Brdt binding and that alternating H4 acetylation and butyrylation could impact the final male epigenome features.
Goudarzi, A. et al. Mol Cell. 2016 Apr 21;62(2):169-80.
doi: 10.1016/j.molcel.2016.03.014.
Abstract.

TRIBE: Hijacking an RNA Editing Enzyme to Identify Cell-Specific Targets of RNA-Binding Protein.
A novel technology for studying which RNA molecules interact with specific RNA binding proteins (RBPs) is presented in this issue of Cell. Taking advantage of the catalytic domain of the RNA editing protein, ADAR, scientists have developed a method called TRIBE (targets of RNA-binding proteins identified by editing). This method is based on the construction of a fusion protein containing an RNA binding protein and the catalytic domain of ADAR. After transfection into cells, RBP targets are marked with novel RNA editing events and identified by RNA-sequencing.
McMahon, A.C. et al. Cell. 2016 Apr 21;165(3):742-53.
doi: 10.1016/j.cell.2016.03.007.
Full Article.
 

April 2016

Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals.
In this recent Science publication, the authors investigate the mechanism by which paternal diet affects offspring metabolism. A low amount protein diet in mice is found to regulate expression of small RNAs such as let-7 and tRNA fragments (tRFs) in the sperm. Additionally, functional tRNA-glycine-GCC fragments are found to be repressing the expression of genes associated with the endogenous retro element MERVL in both embryonic cells and embryos.
Sharma, P. et al. Science. 22 Jan 2016. DOI: 10.1126/science.aad6780
Abstract.

Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism.
In this recent PLoS publication, Lakisic and collaborators examine the physiological role of the BAHD1 protein. In addition to identifying the physical interaction of the BAHD1 and MIER proteins, the authors are able to show that BAHD1-associated complexes induce histone and DNA modifications that subsequently shape repressive chromatin structures; they were also able to identify the importance of this heterochromatic protein in regulating metabolic genes for fetal and placental development as well as cholesterol biosynthesis.
Lakisic et al. PLoS Genetics. 3 March 2016; http://dx.doi.org/10.1371/journal.pgen.1005898.
Full Article.

Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
In this recent Nature publication, Dr. Lin and his collaborators worked with Active Motif to better characterize Medullobastoma subgroups and to create epigenetic profiles of Super Enhancer regions (SE). The results identified differential binding of H3K27Ac and BRD4 in Super Enhancer regions of relevant transcription factors and provided Medulloblastoma-subgroup specific identity.
Lin et al. Nature. 27 Jan 2016: doi:10.1038/nature16546
Abstract.
 

March 2016

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.
In the current issue of Nature Genetics, Bandopadhayay and colleagues use Epigenetics Services and Lightswitch products from Active Motif to identify the basic epigenetic and genetic mechanisms that the MYB-QKI fusion protein uses to promote tumorigenesis in human cells. In vitro and in vivo functional studies indicate that MYB-QKIrearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI.
Bandopadhayay, P. et al. Nat Genet. 2016 Feb 1. doi: 10.1038/ng.3500
Abstract.

Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns.
Folate (vitamin B9) is vital for fetal development and its deficiency is associated with cardiac and neural tube neonatal defects. In this study, the authors use gene expression profiles to examine the relationship between maternal plasma folate during pregnancy and genome-wide differential DNA methylation in newborn cord blood. Hundreds of genes were found to be associated with maternal plasma folate levels during pregnancy, most of which not being known for folate biology. These findings underscore the contribution of the mother’s diet during pregnancy to the epigenomic status and health of her offspring.
Joubert BR. et al. Nature Commun. 2016 Feb 10;7:10577. doi: 10.1038/ncomms10577.
Full Article.

Dynamics of epigenetic regulation at the single-cell level.
In the current issue of Science, Bintu, Yong and collaborators present an original method to study the dynamics of epigenetic regulation and memory at the single cell level. They created a sensitive “chromatin” reporter system that was able to reveal the dynamic state of epigenetic regulation based on different chromatin regulators and verify that distinct modifiers can produce different characteristics of epigenetic memory.
Bintu, L. et al. Science. 12 Feb 2016: Vol. 351, Issue 6274, pp. 720-724, DOI: 10.1126/science.aab2956
Abstract.
 

February 2016

Histone modifications predispose genome regions to breakage and translocation.
In this paper, genome-wide histone modification datasets from a panel of cancer cell lines were used to identify the epigenetic identity of DNA breakage events. The authors were able to associate the presence of active chromatin marks such as H3K4 methylation with regions prone to DNA breakages and translocations. Additionally, by artificially tethering a SET2 methyltransferase-LacI fusion to a lacOp array, they were able to identify the presence of active marks on the lacOp array and an increase in double-stranded breaks (DSB) of DNA at these sites.
Burman et al. Genes & Development. 2015 Jul 1;29(13):1393-402. doi: 10.1101/gad.262170.115. Epub 2015 Jun 23
Abstract.

Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples.
Current DNAse I-seq protocols are limited by their requirement for large numbers of cells. The authors of this paper have established a new protocol applicable to single cell and FFPE tissue samples. This very sensitive technique is called scDNAse-seq and it relies on the presence of a carrier Circular DNA during the sequencing process. Using this method, the authors were able to predict enhancers that regulate cell-specific gene expression and correlate with active histone modification marks. Furthermore, using FFPE samples from patients with thyroid cancers the authors were able to detect DNAse-hypersensitivity sites (DHSs) related to cancer progression.
Zhao K. et al. Nature. 2015 Dec 3;528(7580):142-6. doi: 10.1038/nature15740.
Abstract.

A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes
The authors of this study have developed a multiplexing system for ChIP-Seq that allows for the use of fewer cells. In the resulting protocol, Mint ChIP, indexed samples are pooled and then split for parallel ChIP assays. Using this advanced technology, the authors were able to quantitatively profile multiple epigenetic marks across a series of different cell types and conditions.
Bernstein, BE. et al. Mol. Cell. 2016 Jan 7;61(1):170-80. doi: 10.1016/j.molcel.2015.11.003. Epub 2015 Dec 10.
Abstract.
 

January 2016

Obesity and Bariatric surgery drive Epigenetic Variation of Spermatozoa in Humans
Obesity is a heritable disorder and children of obese fathers have an increased risk of manifesting disease. Environmental factors could alter the epigenetic status of obese fathers but thus far the molecular mechanism of heritability remains poorly understood. Donkin et al show for the first time that spermatozoa in obese men present a series of epigenetic changes. Notably, the expression profile of the scnRNAs that target the genes responsible for behaviour and food intake shows dramatic changes. Additionally, obese men present a distinct methylation pattern of genes controlling brain development and function. Bariatric surgery could alter the DNA methylation landscape of spermatozoa, especially in master genes associated with obesity and nutritional behaviour, thereby determining the epigenetic status of offspring.
Donklin et al. Cell Metab. 2015 Dec 6; pii: S1550-4131(15)00571-9. doi: 10.1016/j.cmet.2015.11.004. [Epub ahead of print]
Short Article.
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Remodeling of retrotransposon elements during epigenetic induction of adult visual cortical plasticity by HDAC inhibitors
A very interesting study highlighting the importance of chromatin regulation in adult visual cortical plasticity. Lennartsson et al utilized HDAc inhibitor (VPA) in order to induce epigenetic alterations in the chromatin of brain cells in the mature visual cortex. After exposure to HDAC inhibitor, remodelling of chromatin leads to the increased accessibility of transcription factors in regulatory regions of brain specific genes and nucleosome eviction in SINEs.
Lennartsson et al. Epigenetics Chromatin. 2015 Dec 14; 8:55. doi: 10.1186/s13072-015-0043-3. eCollection 2015
Full Article.
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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts
This is the first study to evaluate the importance of genomic alterations to the disease aetiology of lung cancer patients by performing a genome-wide methylation analysis in peripheral blood. Although previous studies have shown an association of tobacco exposure and methylation of CPG islands at specific sites, it is not known whether the methylation status of these sites is related to lung cancer. In this study, DNA was extracted from pre-diagnostic blood of 132 pairs of lung cancer cases along with controls from different cohorts and DNA methylation status was determined. The results indicate that exposure to a toxic agent such a smoke results in hypo-methylation of smoking related genes and this status remains stable over series of mitotic divisions in blood cells.
Fasanelli F. et al. Nat. Communications. 2015 Dec 15. doi: 10.1038/ncomms10192
Full Article.
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December 2015

Autophagy mediates degradation of nuclear lamina
Researchers from the Berger lab report on the role of autophagy in tumor suppression and degradation of the nuclear lamina. The interaction of autophagic protein LC3 with lamin B1 mediates lamin B1 degradation only upon ongogenic insults, such as those by activated RAS. This study elucidates a new role of autophagy in protecting cells from tumorigenesis.
Dou Z. et al. Nature. 2015 Nov 5;527(7576):105-9. doi: 10.1038/nature15548. Epub 2015 Oct 28.
Abstract.
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Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.
In recent years, several studies have uncovered roles for new proteins in the maintenance of chromatin assembly and stability. Histone proteins and histone variants are central players in these pathways. In the current study Nashun and colleagues describe the role of the histone chaperone Hira in chromatin accessibility, transcription, and DNA methylation during mouse oogenesis.
Nashun B. et al. Mol. Cell.2015 Nov 4. pii: S1097-2765(15)00777-7. doi: 10.1016/j.molcel.2015.10.010. [Epub ahead of print]
Abstract.
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Protein-RNA networks revealed through covalent RNA marks
In the current study, the authors have developed a novel method to identify RNA-protein interactions in vivo without the need for crosslinking. This method uses an RNA-binding protein of interest fused to an enzyme that adds uridines to the end of RNA. Once covalently marked with uridines, RNA targets are identified by high-throughput sequencing. Using this methodology, the authors were able to identify hundreds of new & likely regulated targets of Puf3p RNA-binding protein.
Lapointe CP. et al. Nat. Methods.2015 Nov 2. doi: 10.1038/nmeth.3651. [Epub ahead of print]
Abstract.
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November 2015

A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation
The authors of this study performed an adapted UV-CLIP protocol, at single nucleotide resolution, on human CD8+ T cells & mouse brains to locate m6 A residues on mammalian mRNA molecules. Results strongly suggest that m6A deposition is triggered, not by proximity to a stop codon, but by entry into the last exon of an mRNA.
Ke et al. (2015) Genes & Development. doi:10.1101/gad.269415.115
Abstract.
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Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state
Two limitations of chromatin mapping technologies are that they rely on large amounts of input material and that they average mixed cell populations. Although technologies for single-cell transcriptome studies are rapidly evolving, chromatin-based experiments in single cells have remained elusive thus far. The authors of this study developed an innovative microfluidics technology including single cell isolation and chromatin immunoprecipitation in order to map differences in epigenetic identity in cell subpopulations.
Rotem A, (2015) Nat. Biotechnol. doi: 10.1038/nbt.3383
Abstract.
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Tracing Dynamic Changes of DNA Methylation at Single-Cell Resolution
In this study, the Jaenisch lab describes a new reporter of genomic methylation (RGM) based on a methylation-sensitive promoter fused to a fluorescent protein. RGM reports on the methylation status of the regulatory elements adjacent to it and can be used to study methylation in single, living cells to visualize heterogeneity within wildtype or cancer specimens. Since the fluorescent proteins used in the study (GFP and tdTomato) have a long half-life, this technique may be further optimized using destabilized fluorescent proteins.
Stelzer et al (2015) Cell. doi: 10.1016/j.cell.2015.08.046
Abstract.
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October 2015

DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts
DNA demethylating agents have shown clinical antitumor efficacy however the underlying mechanism of their function remains unknown. In the latest issue of Cell, David Roulois and collaborators uncover the role of the DNA methylation inhibitor 5-AZA-CdR in targeting colorectal cancer initiating cells (CICs).
Roulois et al. (2015) Cell. doi.org/10.1016/j.cell.2015.07.056
Abstract.
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Genome-wide Maps of Nuclear Lamina Interactions in Single Human Cells
Mammalian interphase chromosomes interact with lamina through well-defined lamin associated domains (LADs). Conformation data from genome-wide chromosome experiments have identified roughly 1000-1400 discrete LADs scattered across all chromosomes. Most of the genes in these LADs are expressed at very low levels and marked with repressive marks. In this study, researchers from Bas van Steensel’s lab have developed a new, high-resolution technology to conduct single cell Dam-ID experiments. Their 395 single cell maps provide insight into how 3D genomic conformation and gene localization varies from cell to cell.
Kind et al. (2015) Cell. doi.org/10.1016/j.cell.2015.08.040
Abstract.
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PARP1- and CTCF-Mediated Interactions between Active and Repressed Chromatin at the Lamina Promote Oscillating Transcription
The circadian clock is an important paradigm of adaptive transcriptional regulation in the cell. Periodic oscillations of gene products controlling cell signalling and metabolism contribute to timing-dependent combinatorial patterns in the proteome. In the current study, authors suggest that PARP1 and CTCF regulate interaction between active and inactive nuclear compartments to connect oscillating 3D chromatin conformations with the metabolic states of the cell.
Zhao et al (2015) Cell. doi.org/10.1016/j.molcel.2015.07.019
Abstract.
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