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Epigenetics News

Sep 2016

Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs.
Drug resistance in cancer treatment continues to be major issue in oncology and recent studies have underlined the importance of chromatin related factors in reversible drug tolerance persistence. In this recent Nature Communications publication, the authors investigate a potential role for microRNAs in transient drug tolerance. By using Active Motif’s genome wide collection of 3´UTRs, the authors were able to uncover the role of miR371-3p as a potent suppressor of drug tolerance by regulating the expression of PRDX6 (peroxiredoxin 6).
Sahu, N. et al: Nature Commun.. 2016 Aug 3;7:12351. doi: 10.1038/ncomms12351

DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy
Using Active Motif’s Epigenetic services for hMeDIP and high throughput sequencing, the authors of this recent Nature Communications publication were able to identify differential 5-hmC DNA modifications between embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes and interestingly, that highly expressed genes related to heart development & failure are marked by DNA hydoxymethylation along the gene bodies and distal regulatory regions.
Greco, C.M. et al: 2016 Aug 4;7:12418. doi: 10.1038/ncomms12418

Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals
In this current issue of Nature Communications, researchers investigate the cross talk between H3K9me2/3 and DNA methylation. In order to study the effects of DNA methylation across the genome, an Uhrf1 knock-in (KI) mouse model has been generated that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. Global effects on DNA methylation have been observed and are not restricted to highly H3k9me2/3 marked regions. Moreover, in vitro UHRF1 binds nucleosome with hemi-mCpGs better than with H3K9me3, thus providing a molecular explanation that UHRF1-mediated DNA maintenance methylation is largely independent of its H3K9me2/3-binding activity.
Zhao, Q. et al: Nature Commun.. 2016 Aug 24;7:12464. doi: 10.1038/ncomms12464

Aug 2016

CTCF contributes in a critical way to spermatogenesis and male fertility
This recent Scientific Reports publication examines the role of the architectural protein CTCF (CCCTC-binding factor) during spermatogenesis. Among other things, the authors show that CTCF inactivation results in impaired spermiogenesis & infertility and that CTCF regulates chromatin compaction and is necessary for packaging of the paternal genome into mature sperm.
Hernández-Hernández A. et al: Sci Rep. 2016 Jun 27;6:28355. doi: 10.1038/srep28355

Comprehensive Identification of RNA-Binding Domains in Human Cells
The Interaction between RNA binding proteins (RBPs) and RNA plays an essential role in RNA metabolism and has implications for many hereditary diseases. In this current issue of Mol. Cell, scientists from M. Hentze’s lab outline RBDmap, which they have developed as a method for the in vivo identification of RBDs on a proteome-wide scale. Using this map, they were able to map 1,174 binding sites within 529 HeLa cell RBPs, discovering numerous RNA-binding domains (RBDs).
Alfredo Castello et al: DOI:

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility
In this current study, Denny and collaborators analyse small cell lung cancer (SCLC) cells from primary tumors and metastases to identify global changes in chromatin accessibility during metastasic progression. Their results indicate that high expression of a single transcription factor, Nfib, alters chromatin state globally and enacts a program of gene expression that promotes multiple steps of the metastatic cascade.
Denny SK et al: Cell. 2016 Jul 14;166(2):328-42. doi: 10.1016/j.cell.2016.05.052. Epub 2016 Jun 30

July 2016

Functional interdependence of BRD4 and DOT1L in MLL leukemia
In this recent publication, the histone methyltransferase DOT1L and the acetylation "reader" BRD4 are found to work synergistically to mediate transcription of cancer genes in leukemia. Using a series of in vivo and in vitro experiments, the authors also discover a functional link between DOT1L and BRD4 binding at H4 acetylated histones. This interaction takes place close to super-enhancer regions in highly transcribed genes and provides new insights into the regulation of transcription.
Gilan, O. et al. Nat Struct Mol Biol. 2016 Jun 13. doi: 10.1038/nsmb.3249

Mapping RNA–RNA interactome and RNA structure in vivo by MARIO
Scientists from University of California, San Diego present the novel Mapping RNA interactome in vivo (MARIO) technology, which is capable of revealing RNA–RNA interactions from unperturbed cells on a massive scale. Using a crosslinking approach, the authors were able to capture interactions of different molecules of RNA in close proximity, mediated by protein binding in vivo. In addition, MARIO data reveal thousands of intra-molecule interactions, providing in vivo data on high-order RNA structures
Nguyen, T.C. et al. Nat Commun. 2016 Jun 24;7:12023. doi: 10.1038/ncomms12023.

MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency
Epiblast Stem Cells (EpiSC) reprograming is associated with a drastic alteration of the epigenetic landscape but mechanistic studies showing the precise changes that occur at the molecular level during reprogramming remain sparse. In the current issue of Cell Stem Cell scientists from the lab of Yali Dou were able to demonstrate the role of the MLL1 histone methyltransferase in EpiSC conversion to “naïve” pluripotent stem cells. Using a specific inhibitor against the MLL1 enzyme they were able to re-activate the silenced X-chromosome. Moreover, they observed a global redistribution of the H3K4me1 active mark, which is directly linked to gene expression programs responsible for stem cell reprogramming.
Zhang, H. et al. Cell Stem Cell. 2016 Apr 7;18(4):481-94. doi: 10.1016/j.stem.2016.02.004. Epub 2016 Mar 17

June 2016

Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers
In the current issue of Molecular Cell, researchers from the P. Jones lab investigate the role of DNA methylation in enhancer regions. By comparing the epigenomes of the HCT116 and DKO1 cell lines, they were able to identify that a portion of regular and super- or stretch enhancers show active H3K27ac marks co-existing with extensive DNA methylation. Additionally, DNA methylation appears to play an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor-binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity.
Charlet, J. et al. Mol. Cell. 2016 May 5;62(3):422-31 doi: 10.1016/j.molcel.2016.03.033.

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA
In this recent publication, researchers investigate and quantify the impact of chronic HIV infection on aging. Using 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals, a global analysis of the whole-blood DNA methylomes was conducted. Using epigenetic models that were created and validated, it was found that chronic and recent HIV infection lead to an average aging advancement of 4.9 years and increased expected mortality risk by 19%. Additionally, decreased HLA methylation was found to be predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression.
Gross, A.M. et al. Mol Cell. 2016 Apr 21;62(2):157-68 doi: 10.1016/j.molcel.2016.03.019

Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk
In this recent Cell publication, researchers in the Hunter Fraser lab introduce a pooling-based approach to mapping quantitative trait loci (QTLs) for molecular-level traits. Applying this method to five transcription factors (TFs) and a histone modification, they were able to map thousands of cis-acting QTLs, with over 25-fold lower cost compared to standard QTL mapping.
Tehranchi, A.K. et al. Cell. 2016 Apr 21;165(3):730-41 doi:10.1016/j.cell.2016.03.041. Epub 2016 Apr 14

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. Epub 2016 Mar 30.

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.

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. Epub 2016 Mar 31
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

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;
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

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

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

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

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.

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.

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.
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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]
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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]
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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
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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
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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
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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.
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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.
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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.
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