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November 2018

Exposure to Childhood Abuse is Associated With Human Sperm DNA Methylation
In the current issue of Translational Psychiatry, Dr. Roberts and collaborators studied the epigenetic memory of the offspring of persons exposed to childhood abuse due to a differential DNA methylation profile. Their data support the hypothesis that DNA methylation marks in certain protein coding regions correlate with a higher risk of neurodevelopmental and physical health disparities across the course of a lifetime.

DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal, non-clinical cohort using HumanMethylation450 BeadChips. Several differentially methylated regions (DMRs) were identified in protein coding gene regions. These genes have a variety of functions ranging from fat metabolism to immune response. Surprisingly, 5 unique DMRs were observed that highly correlate with trauma exposure and higher prevalence of depressive and posttraumatic stress symptoms in men who experienced childhood abuse.

Roberts, A.L. et al: Translational Psychiatry. 8(1), 194 (2018)
DOI: 10.1038/s41398-018-0252-1
Link to publication.

Chromatin Accessibility Landscape of Articular Knee Cartilage Reveals Aberrant Enhancer Regulation in Osteoarthritis
In the current issue of Scientific Reports, scientists employed ATAC-seq analysis to investigate chromatin signatures in articular cartilage associated with Osteoarthritis (OA).

Osteoarthritis (OA) is a degenerative joint disease that is one of the most common causes of chronic disability in the world, of which OA in the knee is the most common. Several studies have yet to fully reveal the underlying molecular mechanism of how the transcription of these genes is dysregulated. Here, the authors set out to investigate alterations of enhancers associated with OA by applying ATAC-seq analysis to knee joint cartilage from OA patients, using an optimized protocol for cartilage sample preparation. ATAC-seq maps accessible chromatin regions, which are often regulatory regions such as promoters and enhancers that play roles in the regulation of gene expression.

The data highlights a number of loci associated with OA risk that potentially play roles in cartilage degradation during OA development.

Liu, Y.et al: Scientific Reports 8(1), 15499 (2018)
DOI: 10.1038/s41598-018-33779-z
Link to publication.

Transcription Factor Sp2 Potentiates Binding of the TALE Homeoproteins Pbx1:Prep1 and the Histone-fold Domain Protein Nf-y to Composite Genomic Sites
Transcription factors use a repertoire of different approaches to the binding of DNA. The most common way of targeting is based on their binding motif that recognizes specific DNA sequences. However, only a small fraction of DNA binding motifs in the genome are occupied by the corresponding transcription factor that determines binding. Indeed, many transcription factors can be recruited to a promoter as part of a protein complex in the context of chromatin accessibility. In this recent article, authors have used a high resolution ChIP seq protocol, ChIP-exo, which combines the conventional ChIP technique with the activity of an exonuclease, increasing DNA resolution. This helps to precisely map transcription factor binding and define potential DNA motifs.

Using the transcription factor Sp2 as an example, they were able to reveal a mechanism of DNA loading, in which the DNA binding-independent activity of Sp2 potentiates genomic loading of Pbx1:Prep1 and Nuclear Factor y (Nf-y) to compose motifs that are present in many promoters of highly expressed genes.

Völkel, S. et al: J Biol Chem, Epub 2018 October 18.
DOI: 10.1074/jbc.RA118.005341
Link to publication.
 

October 2018

Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
In the latest issue of Cell, Phillips-Cremins and team discovered that the vast proportion of all disease-associated short tandem repeats (daSTRs) are located at TAD and subTAD boundaries, with particular preference for those boundaries exhibiting ultra-high CpG island density. Unstable expansion of STRs is the basis of over 25 inherited human disorders, including fragile X syndrome.

The authors also found that B cells, fibroblasts, and postmortem brain tissue derived from fragile X syndrome patients showed severe alterations of TAD boundaries. Particularly relevant for the etiology of this disease, the authors observed that boundary disruption alters the genome topology around the FMR1 gene, resulting in its pathologic silencing. Boundary disruption therefore represents a potential causative mechanism for a wide range of diseases, from repeat expansion disorders to cancer.

Sun James H. et al: Cell. 175(1), 224-238 (2018)
DOI: 10.1016/j.cell.2018.08.005
Link to publication.

Functional Classification of Long Non-coding RNAs by k-mer Content
In this current issue of Nature Genetics, authors present a novel method for functional classification of long non coding RNAs.

There is a high interest in trying to predict the function of lncRNAs based on their sequence. However, this task is complicated by the fact that, unlike proteins, lncRNAs sharing similar function do not appear to show linear sequence homology. In this study Kirk and colleagues use a novel approach to resolve this problem by searching lncRNAs for patterns in short motifs called k-mers rather than similarity in linear sequence. They found that lncRNAs of similar function had very closely related k-mer profiles. Crucially, lncRNAs exhibiting related k-mer signatures could be found in human, mouse, and even other organisms, meaning this method could be used to identify functionally similar lncRNAs in different species.

As a conclusion, authors believe that the common k-mers represent protein-binding motifs within lncRNA. The ability to better predict lncRNA function from its sequence using this new methodology will greatly accelerate our ability to pinpoint interesting lncRNA targets.

Kirk, J.M.et al: Nature Genetics 50, 1474-1482 (2018)
DOI: 10.1038/s41588-018-0207-8
Link to publication.

Transcriptional Addiction in Cancer Cells is Mediated by YAP/TAZ Through BRD4
In this recent Nature Medicine publication, scientists are dealing with a new and intriguing concept in cancer biology related to ‘transcriptional addiction’. Cancer cells, in order to achieve uncontrolled proliferation or other needs, set high demands on transcriptional regulators, and even the basal transcriptional machinery. The molecular mechanisms underlying the transcriptional dependency of cancer cells to date, have been poorly understood and defined.

Here, they focus on the transcriptional coactivators YAP (Yes-associated protein)/ TAZ (transcriptional coactivator with PDZ-binding motif) as prominent candidates for transcription addiction. In fact, YAP/TAZ activation is a hallmark of many human malignancies. Using a series of in vivo and in vitro assays the were able to uncover the physical and functional association between YAP/TAZ and BRD4: YAP/TAZ-bound enhancers recruit BRD4, leading to BRD4 accrual on their target promoters boosting the expression of the growth genes.

Zanconato, F. et al: Nature Medicine, Epub 2018 September 17.
DOI: 10.1038/s41591-018-0158-8
Link to publication.
 

September 2018

A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage
In the current issue of Cell Reports Dr. Vazquez and collaborators provide molecular evidence for an evolutionary mechanism developed in large body size and long lifespan mammals, which protects cells from cancer progression through apoptosis. The multifunctional interleukin-6 class cytokine leukemia inhibitory factor (LIF), for example, can function as either a tumor suppressor or an oncogene, depending on the context, and induce caspase induced apoptosis through an unknown mechanism. By studying LIF duplications in 53 mammalian genomes, researchers were able to identify that an elephant pseudogene called LIF6 was transcribed and completely functional (zombie gene) in response to DNA damage. LIF6 is upregulated, translocated to mitochondria, and Induces Mitochondrial Dysfunction and Caspase-Dependent Apoptosis viaTP53 signaling. More precisely upon DNA damage TP53 binds LIF6 and upregulates its transcription.

Vasquez, J. M. et al: Cell Reports. 24(7), 1765-1776 (2018)
DOI: 10.1016/j.celrep.2018.07.042
Link to publication.

Integrative epigenomic analysis in differentiated human primary bronchial epithelial cells exposed to cigarette smoke
In the current issue of Scientific Reports, scientists are using global epigenomic analysis in order to investigate the effect of the cigarette smoke (CS) on bronchial epithelial cells in the epigenome. Elucidation of the chromatin landscape during CS exposure changes as a result of the exposure to the toxic substances of the smoke and could explain the development of lung diseases and cancer.Using Chromatin Immunoprecipitation (ChIP) experiments with an antibody against the histone modification H3K27Ac in both treated and untreated samples, researchers were able to identify changes in regulatory regions in genes related with cellular stress response, macromolecular catabolic processes and cell death, consistent with activation of autophagy and apoptosis pathway by CS exposure.

Glass, K. et al: Scientific Reports. 2018 Aug 24
DOI: 10.1038/s41598-018-30781-3
Link to publication.

High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations
Hematopoietic stem cells (HSCs) are functionally defined cells that display evidence of extensive self-renewal of their ability to generate mature blood cells for the lifetime of the organism. Many studies have revealed the importance of epigenetic mechanisms in normal hematopeoiesis. However, most of the epigenetic measurements underpinning these observations represent consensus values experimentally derived from thousands of cells. In this current study published in Stem Cell Reports, scientists have described a novel protocol in which index-sorted murine and human hematopoietic cells that are highly enriched in their content of functionally defined stem cells followed by single cell DNA bisulfite sequencing. Based on a detailed methylome analysis from single-CpG measurements without the need to infer adjacent methylation states they were able to uncover for the first time, distinct subpopulations of hematopoietic stem cells.

Hui, T. et al: Stem Cell Reports. 11(2), 578-592 (2018).
DOI: 10.1016/j.stemcr.2018.07.003
Link to publication.
 

August 2018

The Role of m6A/m-RNA Methylation in Stress Response Regulation
In the current issue of Neuron, Engel et al examine the stress response of N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) in adult mouse brain tissue and find that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.

Engel, M. et al: Neuron. 2018 Jul
DOI: 10.1016/j.neuron.2018.07.009
Link to publication.

Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association
In this recent study from the journal Leukemia, the authors perform quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA. Their findings indicate that epigenetic and genetic aberrations underlay AML-related changes in DNA methylation at CG-rich regions and that the former may provide a marker to improve classification and prognostication of adult AML patients.

Gebhard, C. et al: Leukemia. 2018 Jun 20
DOI: 10.1038/s41375-018-0165-2
Link to publication.

Early alteration of epigenetic-related transcription in Huntington’s disease mouse models
From the pages of Scientific Reports, this publication describes the underlying epigenetic mechanism that regulates the altered transcription program in Huntington´s disease mouse models and the authors propose that the neuronal epigenetic status is compromised in the prodromal stages of HD, leading to an altered transcriptional programme that is prominently involved in neuronal identity.

Hervás-Corpión, I. et al: Scientific Reports. 8, 9925 (2018).
Link to publication.
 

July 2018

The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression
In the current issue of Molecular Cell, Bornelöv and collaborators investigate the role of the Nucleosome Remodeling and Deacetylation Complex (NuRD) and show that this complex controls chromatin architecture and the protein binding repertoire at regulatory regions during cell state transitions.

Bornelöv, S. et al: Mol Cell. 2018 Jun 28
doi.org/10.1016/j.molcel.2018.06.003
Link to publication.

Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
In the current issue of Nature Communications, scientists investigate the epigenetic modifier Ezh2 and find that genetic or pharmacological targeting of this modifier dramatically hinders metastatic behavior in both a mouse model of breast cancer and patient-derived xenografts.

Hirukawa, A. et al: Nature Communications. 2018 Jun 29;9(1):2547
DOI: 10.1038/s41467-018-04864-8
Link to publication.

Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells
This recent Nature publication describes an unusual case in which CAR T cell therapy was used to treat chronic lymphocytic leukaemia (CLL) and emphasizes the importance of the usage of epigenetic targeting mechanisms in order to improve the efficacy of the therapy.

Fraietta, J.A. et al: Nature. 2018 May 30; 558,307-312(2018).
DOI: 10.1038/s41586-018-0178-z
Link to publication.
 

June 2018

3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk.
In the current issue of Nature Genetics, Park and collaborators investigate the role of 3´ UTR shortening in tumor growth and report a surprising enrichment of 3'UTR shortening among transcripts that are predicted to act as competing-endogenous RNAs (ceRNAs) for tumor-suppressor genes. Their findings also suggest a major role of 3' UTR shortening in repressing tumor-suppressor genes in trans by disrupting ceRNA crosstalk, rather than inducing proto-oncogenes in cis.

Park, H.J. et al: Nat Genet. 2018 Jun;50(6):783-789. Epub 2018 May 21.
doi: 10.1038/s41588-018-0118-8. Link to PubMed ID: 29785014.

A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer.
In this recent Nucleic Acids Research publication, this group from S. Forcales lab investigates the role of a novel non-coding RNA in colon cancer progression and finds novel DNA and RNA structural features of a non-coding microsatellite that are frequently altered in cancer.

Dumbovic, G. et al: Nucleic Acids Research. 2018 Apr 18
doi.org/10.1093/nar/gky263 Link to publication.

Epigenetic regulation of transcriptional plasticity associated with developmental song learning.
In collaboration with the London lab from the University of Chicago, this team from Active Motif used ChIP-Seq, RNA-Seq, and molecular biology to determine that naturalistic experiences associated with the ability to learn can induce epigenetic changes, and they propose that transcriptional plasticity is a mediator of critical period learning potential.

Kelly, T.K. et al: Proc. Biol. Sci. 2018 May 16; 285(1878). pii:20180160
DOI: 10.1098/rspb.2018.0160. Link to Pub Med ID: 29720411.
 

May 2018

An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance.
The authors of this recent Cell publication are focused on the genetics that govern resistance to Cytarabine (Ara-C), the gold standard chemotherapy for the treatment of acute myeloid leukemia (AML). They have developed a comprehensive genome-wide platform based on a dual protein-coding and non-coding integrated CRISPRa screening (DICaS) to identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for acute myeloid leukemia (AML).

Bester, A.C. et al: Cell. 2018 Apr 19. 173(3):649-664.e20.
doi: 10.1016/j.cell.2018.03.052.
Link to PubMed ID: 29677511.

Cavitation Enhancement Increases the Efficiency and Consistency of Chromatin Fragmentation from Fixed Cells for Downstream Quantitative Applications.
In this study from the current issue of Biochemistry, the authors present a novel method for more efficient and consistent chromatin fragmentation from fixed cells. This method relies on a cavitation enhancing reagent that is based on sonically active nanodroplets, which are shown to increase sonication efficiency by 16-fold while providing more consistent levels of chromatin fragmentation.

Chiarella, A.M.et al: Biochemistry. 2018 Apr 25 [Epub ahead of print]
DOI: 10.1021/acs.biochem.8b00075 Link to PubMed ID: 29658277.

Global profiling of protein–DNA and protein–nucleosome binding affinities using quantitative mass spectrometry.
In this recent Nature Communications article, the authors introduce a novel Mass Spec method for quantitative protein-DNA and protein–nucleosome interactions. This method uses affinity purifications from nuclear extracts coupled with chemical labeling and mass spectrometry to quantify apparent binding affinities of mono- & multimeric transcription factors and chromatin remodeling complexes.

Makowski, M. et al: Nature Communications. 2018 Apr 25; Art. Num. 1653.
doi:10.1038/s41467-018-04084-0. Link to Pub Med ID: PMC5036873.
 

April 2018

Promoter-associated proteins of EPAS1 identified by enChIP-MS - A putative role of HDX as a negative regulator.
In this soon-to-be published study, Hamidian et al employ the novel CRISPR/Cas9-based engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) - mass spectrometry (MS) methodology to identify proteins that associate with the EPAS1 promoter under normoxic and hypoxic conditions.

Hamidian, A. et al: Biochem Biophys Res Commun.. 2018 Mar 22.
pii: S0006-291X(18)30662-4. doi: 10.1016/j.bbrc.2018.03.150.
[Epub ahead of print] Link to PubMed ID: 29577908.

RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
The authors of this study from the current issue of Nature Communication investigate the roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in chromatin organization and drug response/resistance in leukemia.

Cheng, J.X..et al: Nat Commun. 2018 Mar 21;9(1):1163.
doi: 10.1038/s41467-018-03513-4. Link to PubMed ID: 29563491.

Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites.
In the current study published in Science, the authors mapped strand-specific DNA methylation after replication forks and showed maintenance of the vast majority of the DNA methylome within 20 minutes of replication and inheritance of some hemimethylated CpG dinucleotides (hemiCpGs).

Xu, C. et al: Science. 2018 Mar 9;359(6380):1166-1170.
doi: 10.1126/science.aan5480. Link to Pub Med ID: 29590048.
 

March 2018

Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.
In the current issue of Nature Cell Biology, Huang and collaborators report a novel role of the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs, IGF2BP1/2/3). This distinct family of m6A readers targets the consensus GG(m6A)C sequence on thousands transcripts including MYC & IGF2BP and in doing so, can regulate mRNA storage and decay, influencing gene expression output.

Huang, H. et al: Nature Cell Biology. 2018 Feb 23;20(285-295).
doi:10.1038/s41556-018-0045-z. Link to PubMed ID: 29476152.

A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.
In the current issue of Cell, Hoshii et al use a series of CRISPR-Cas9 mutagenesis screening experiments to identify a novel functional region called the "FLOS" (the functional location on SETD1) that is responsible for survival of acute myeloid leukemia (AML) cells. This region acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. Overall this study reveals a novel role of the SETD1 methyltransferase independent of its enzymatic function responsible for histone methylation.

Hoshii, T.et al: Cell. 2018 Feb 22;172(5)1007-1021.e17
doi: 10.1016/j.cell.2018.01.032. Link to PubMed ID: 29474905.

scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells.
In the current study published in Nature Communications, scientists from W. Reik´s lab present a novel, single-cell method for parallel chromatin accessibility, DNA methylation and transcriptome profiling. This method, which they've dubbed scNMT-seq (single-cell nucleosome, methylation and transcription sequencing), uses a GpC methyltransferase to label open chromatin followed by bisulfite and RNA sequencing.

Clark, S.J. et al: Nature Communications. 2018 Jan 23;
doi:10.1038/s41467-018-03149-4. Link to Pub Med ID: 29472610.
 

February 2018

Epigenetic control of influenza virus: role of H3K79 methylation in interferon-induced antiviral response.
This original research elucidates the role of basic epigenetic mechanisms in the defense against influenza virus infection. H3K79 methylation defines host gene expression involved in metabolic pathways upon infection. By downregulating levels of Dot1 methyltransferase, researchers could interfere with the interferon-induced antiviral response and thereby augment virus replication; they were also able to show that histone-specific methylation has a prominent role in response to influenza infection.
Marcos-Villar, L. et al: Scientific Reports. 2017 Dec 29;8(1230). doi:10.1038/s41598-018-19370-6.
Abstract.

Epigenetic supersimilarity of monozygotic twin pairs.
In the current issue of Genome Biology, researchers examine monozygotic twins to try to identify regions of "epigenetic supersimilarity"; that is, genomic regions at which the epigenetic similarity of monozygotic twins is substantially greater than can be explained by their genetic identity. Using publicly available data of DNA methylation on CpG islands, the researchers located “super-similar” epigenetic loci in monozygotic twins, mostly located in sub-telomeric regions. Methylation at these loci was found to be stable from embryonic stages through adulthood and is associated with risk of developing several cancer types. This study reveals a new level of epigenetic similarity in monozygotic twins, which is connected to human disease epidemiology.
Van Baak, T.E. et al: Genome Biology. 2018 Jan 9;19(1)2 DOI: 10.1186/s13059-017-1374-0.
Abstract.

Structural Basis of Heterochromatin Formation by Human HP1.
In the current issue of Molecular Cell, scientists have resolved the structure of H3K9me3-containing dinucleosomes in complex with human HP1α, HP1β, and HP1γ, therefore depicting the structural formation of heterochromatin in eukaryotic cells. The structure clearly shows two H3K9me3 nucleosomes bridged by a symmetric HP1 dimer and interestingly, the linker DNA between the two nucleosomes does not interact with HP1, allowing it to remain accessible to nucleosome remodeling machinery.
Machida, S. et al: Molecular Cell. 2017 Dec 13; doi.org/10.1016/j.molcel.2017.12.011.
Abstract.
 

January 2018

YY1 Is a Structural Regulator of Enhancer-Promoter Loops.
In the current issue of Cell, Weintraub et al show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF, and propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
Weintraub A.S. et al: Cell. 2017 Dec 14;171(7):1573-1588.e28. doi: 10.1016/j.cell.2017.11.008. Epub 2017 Dec 7.
Abstract.

DNA methylation signal has a major role in the response of human breast cancer cells to the microenvironment.
In this recent Oncogenesis publication, the authors investigate the mechanisms underlying changes in gene expression patterns associated with the cross-talk between breast cancer cells and the stroma. The results highlight the importance of epigenetics marks in cancer cell reprogramming induced by stromal cells and indicate that the interpreters of the DNA methylation signal play a major role in the response of the cancer cells to the microenvironment.
Mathot, P. et al: Oncogenesis. 2017 Oct 23;6(10):e390. doi: 10.1038/oncsis.2017.88.
Abstract.

Prognostic Value of Long Non-Coding RNA HULC and MALAT1 Following the Curative Resection of Hepatocellular Carcinoma.
In the current issue of Scientific Reports, scientists investigate the importance of non-coding RNAs (ncRNAs) as a prognostic tool. Using microarray analysis of ncRNA expression in Hepatocellular carcinoma (HCC) cells, the authors found increased expression levels of HULC and MALAT1 in the normal background tissue of HCC as compared to the normal liver tissue of metastatic liver tumor without hepatitis.
Sonohara, F. et al: Sci Rep. 2017 Nov 23;7(1):16142. doi: 10.1038/s41598-017-16260-1.
Abstract.
 

December 2017

Histone Acetylome-wide Association Study of Autism Spectrum Disorder.
In the current issue of Cell, scientists conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac ChIP-Seq on 257 postmortem samples from patients with Autism spectrum disorder (ASD). This study elucidates the association of the histone acetylome signature in ASD and introduces a new way to characterize multiple disorders.
Sun W. et al: Cell. 2016 Nov 17;167(5):1385-1397.e11. doi: 10.1016/j.cell.2016.10.031..
Abstract.

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation.
In the current study, the authors use a meta-epigenomic approach that combines DNA methylation profiles from many small pools of cells along with single-cell methylome sequencing to assess cell-to-cell heterogeneity. The authors have established a comprehensive catalog of DNA methylation in human hematopoietic differentiation, which provides a detailed map for studying the different cell types of the blood, as well as their associated diseases.
Farlik, M. et al: Cell Stem Cell. 2016 Dec 1;19(6):808-822. doi: 10.1016/j.stem.2016.10.019. Epub 2016 Nov 17.
Abstract.

Histone methyltransferase SUV39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB.
In the current study, scientists report a novel defense mechanism against mycobacterial infection that utilizes the histone methyltransferase, SUV39H1. Normally a part of the host chromatin, SUV39H1 was also found to be associated with the mycobacterial bacilli during infection and it was noted that the ability of mycobacteria to form biofilms was dramatically reduced in the presence of SUV39H1.
Yaseen, I. et al: EMBO J. 2017 Nov 23. pii: e201796918. doi: 10.15252/embj.201796918. [Epub ahead of print.
Abstract.
 

November 2017

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells.
X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. In this current study, the authors investigate the role of Xist during B cell maturation and their results support a two step process model, in which YY1 zinc finger protein is sufficient to restore Xist RNA localization during B cell activation.
Syrett, C.M. et al: PLoS Genetics. 2017 Oct 9;13(10):e1007050. doi: 10.1371/journal.pgen.1007050.
Abstract.

YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer.
Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. In this recent Nature Communications publication, the authors show that the YEATS2 gene is highly amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell growth and survival. By combining a series of in vivo and in vitro experiments, the authors also identify a novel role of YETS2 as a reader of H3K27Ac and promoter of active genes essential for NSCLC tumorigenesis.
Mi, W. et al: Nature Communications. 2017 Oct 20;8(1):1088. doi: 10.1038/s41467-017-01173-4.
Abstract.

Isoform‐specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands.
DNA methylation is a prevalent epigenetic modification involved in transcriptional regulation and is essential for mammalian development. While the genome‐wide distribution of this mark has been studied to great detail, the mechanisms responsible for its correct deposition, as well as the cause for its aberrant localization in cancers, have not been fully elucidated. Here, the authors compare the activity of individual DNMT3A isoforms in mouse embryonic stem and neuronal progenitor cells and report that these isoforms differ in their genomic binding and DNA methylation activity at regulatory sites.
Manzo, M. et al: EMBO J. 2017 Oct 26. pii: e201797038 doi: 10.15252/embj.201797038.
Abstract.
 

October 2017

The Cohesin Complex Is Necessary for Epidermal Progenitor Cell Function through Maintenance of Self-Renewal Genes.
Adult stem and progenitor cells are critical for replenishing lost tissue due to injury or normal turnover. How these cells maintain self-renewal and sustain the tissue they populate are areas of active investigation. Here, we show that the cohesin complex, which has previously been implicated in regulating chromosome segregation and gene expression, is necessary to promote epidermal stem and progenitor cell self-renewal through cell-autonomous mechanisms. Cohesin binds to genomic sites associated with open chromatin, including DNase-I-hypersensitive sites, RNA polymerase II, and histone marks such as H3K27ac and H3K4me3. Reduced cohesin expression results in spontaneous epidermal differentiation due to loss of open chromatin structure and expression of key self-renewal genes. Our results demonstrate a prominent role for cohesin in modulating chromatin structure to allow for enforcement of a stem and progenitor cell gene expression program
Noutsou M. et al: Cell Reports. 2017 Sep 26. 20(13):3005-3013. doi: 10.1016/j.celrep.2017.09.003.
Abstract.

Genetic and epigenetic features direct differential efficiency of Xist-mediated silencing at X-chromosomal and autosomal locations.
Xist is indispensable for X chromosome inactivation. However, how Xist RNA directs chromosome-wide silencing and why some regions are more efficiently silenced than others remains unknown. Here, we explore the function of Xist by inducing ectopic Xist expression from multiple different X-linked and autosomal loci in mouse aneuploid and female diploid embryonic stem cells in which Xist-mediated silencing does not lead to lethal functional monosomy. We show that ectopic Xist expression faithfully recapitulates endogenous X chromosome inactivation from any location on the X chromosome, whereas long-range silencing of autosomal genes is less efficient. Long interspersed elements facilitate inactivation of genes located far away from the Xist transcription locus, and genes escaping X chromosome inactivation show enrichment of CTCF on X chromosomal but not autosomal loci. Our findings highlight important genomic and epigenetic features acquired during sex chromosome evolution to facilitate an efficient X chromosome inactivation process.
Loda, A. et al: Nature Communications. 2017 Sep 25. 8(1):690. doi: 10.1038/s41467-017-00528-1.
Abstract.

MiR-181a inhibits non-small cell lung cancer cell proliferation by targeting CDK1.
MicroRNAs (miRNAs) emerge as important regulators involved in malignant progression in some tumors. MiR-181a has been found to function as a tumor suppressor in some tumors including non-small cell lung cancer (NSCLC). However, the functional role of miR-181a in NSCLC still needed to be investigated. METHODS: The expression of miR-181a were determined by qRT-PCR, the association between miR-181a and clinicopathological data were performed by chi-square test and survival analysis were evaluated by Kaplan-Meier curve and log rank test. Cell proliferation and invasion were assessed by CCK8, cell colony formation and transwell assays. Luciferase reporter assay demonstrated that CDK1 was a target of miR-181a. Western blot assay detected the relative protein expression. RESULTS: In the study, our results showed that miR-181a was significantly down-regulated in non-small cell lung cancer (NSCLC) tissues and cell lines. MiR-181 expression levels were significantly associated with histological grade, N status and TNM stage in the patients and lower miR-181a predicted a poor prognosis in NSCLC patients. Furthermore, upregulation of miR-181a significantly suppressed the NSCLC cell proliferation, colony formation, and cell invasion capacities. Moreover, upregulation of miR-181a inhibited CyclinB1 and CyclinD1 expression in NSCLC cells. Luciferase activity assay results demonstrated CDK1 was a direct target of miR-181a and miR-181a inhibited cell proliferation by regulating the mRNA and protein levels of CDK1 in NSCLC cells. CONCLUSION: These data suggested that miR-181a plays a tumor suppressor and may be a potential therapeutic target for NSCLC patients.
Shi, Q. et al: Cancer Biomarkers. 2017 Sep 8. doi: 10.3233/CBM-170350. [Epub ahead of print]
Abstract.
 

September 2017

An integrated expression atlas of miRNAs and their promoters in human and mouse.
In this recent Nature Biotechnology publication, de Rie at al create an integrated expression atlas of miRNAs and their promoters in primary mammalian cells and in doing so, establish a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.
de Rie, D. et al: Nature Biotechnology. 2017 Aug 21. doi: 10.1038/nbt.3947.
Abstract.

5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes.
In this recent PNAS publication, the authors investigate the functional role of 5-hydroxymethylcytosine (5hmC) in postmitotic neurons and conclude that 5hmC functionally demethylates expressed gene bodies while retaining the role of MeCP2 in chromatin organization.
Mellen, M. et al: Proceedings from the Natl. Academy of Sciences. 2017 Aug 28. pii: 201708044. doi: 10.1073/pnas.1708044114
Abstract.

LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo.
In the current issue of Nature Genetics, scientists from Dr. Torres-Padilla´s lab investigate the functional role of LINE-1 retrotransposon in mammalian development and find that LINE-1 regulates global chromatin accessibility at the beginning of development and that retrotransposon activation is integral to the developmental program.
Jachowicz, J. et al: Nature Genetics. 2017 Aug 28. doi: 10.1038/ng.3945
Abstract.
 

August 2017

ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells.
In the current issue of Science, Ou et al describe a DNA-labeling method, ChromEMT, that allows them to visualize chromatin organization in human cells. This methodology combines electron microscopy tomography (EMT) with a labeling method (ChromEM) that selectivity enhances the contrast of DNA. The authors were able to describe Chromatin as more flexible and disordered in contrast to the current model, forming a 5- to 24-nm-diameter granular chain that is packed together at different concentration densities in interphase nuclei and mitotic chromosomes.
Ou, H.D. et al: Science. 2017 July 28. DOI: 10.1126/science.aag0025
Abstract.

Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer.
In this recent study, Kritsch et al use Active Motif’s Methyl Collector assay to screen for hyper-methylated genes that are resistant to cisplatin treatment in epithelial ovarian cancer. Genome-wide analyses of hypermethylated CpG-islands in resistant cell lines, in combination with qRT-PCR analyses, were performed in order to identify epigenetically silenced genes. Tribbles 2 (TRIB2), a pseudokinase of unknown function, was found to be hypermethylated and downregulated during cisplatin resistance development.
Kritsch, D. et al: Int J Cancer. 2017 Jul 3. doi: 10.1002/ijc.30860
Abstract.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.
In the current issue of Nature, Zhang and collaborators investigate the role the hypothalamus plays in controling ageing. Through the development of several mouse models, the authors conclude that ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.
Zhang, Y. et al: Nature. 2017 Jul 26. doi: 10.1038/nature23282
Abstract.
 

July 2017

Identification of physical interactions between genomic regions by enChIP-Seq.
Physical interactions between genomic regions play critical roles in the regulation of genome functions, including gene expression. However, the methods for confidently detecting physical interactions between genomic regions remain limited. This recent study demonstrates the feasibility of using engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) in combination with next-generation sequencing to detect physical interactions between genomic regions.
Fujita, T. et al: Genes to Cells. 2017 May 5. doi: 10.1111/gtc.12492. [Epub ahead of print]
Abstract.

DUX-family transcription factors regulate zygotic genome activation in placental mammals.
In animal embryos, transcription is mostly silent for several cell divisions, until the release of the first major wave of embryonic transcripts through so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio, but their mammalian homologs remain undefined. This recent Nature Genetics publication provides evidence that the DUX family of transcription factors is essential to the ZGA process in mice and potentially in humans.
De Iaco, A. et al: Nature Genetics. 2017 Jun;49(6):941-945. doi: 10.1038/ng.3858. Epub 2017 May 1.
Abstract.

Simultaneous overactivation of Wnt/b-catenin and TGFb signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC.
Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). This recent Nature Communications article shows that high levels of microRNA-128-3p (miR-128-3p) are key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and that these high levels also correlate with chemoresistance, aggressiveness and poor prognosis in NSCLC patients.
Cai, J. et al: Nature Communications. 2017 Jun 19;8:15870. doi: 10.1038/ncomms15870
Abstract.