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  1. Article ; Online: The epigenetics of early life adversity and trauma inheritance: an interview with Moshe Szyf.

    Szyf, Moshe

    Epigenomics

    2021  Volume 14, Issue 6, Page(s) 309–314

    Abstract: In this interview, Professor Moshe Szyf speaks with Storm Johnson, Commissioning Editor for ...

    Abstract In this interview, Professor Moshe Szyf speaks with Storm Johnson, Commissioning Editor for
    MeSH term(s) Adverse Childhood Experiences ; Canada ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; Humans ; Male
    Language English
    Publishing date 2021-12-08
    Publishing country England
    Document type Interview
    ZDB-ID 2537199-X
    ISSN 1750-192X ; 1750-1911
    ISSN (online) 1750-192X
    ISSN 1750-1911
    DOI 10.2217/epi-2021-0483
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  2. Article ; Online: Genetic confounds of transgenerational epigenetic inheritance in mice.

    Sapozhnikov, Daniel M / Szyf, Moshe

    Epigenetics

    2024  Volume 19, Issue 1, Page(s) 2318519

    Abstract: Transgenerational epigenetic inheritance in mammals remains a controversial phenomenon. A recent study by Takahashi et al. provides evidence for this mode of inheritance in mice by using a CRISPR/Cas9-based epigenetic editing technique to modify DNA ... ...

    Abstract Transgenerational epigenetic inheritance in mammals remains a controversial phenomenon. A recent study by Takahashi et al. provides evidence for this mode of inheritance in mice by using a CRISPR/Cas9-based epigenetic editing technique to modify DNA methylation levels at specific promoters and then demonstrating the inheritance of the gain in methylation in offspring. In this technical commentary, we argue that the method used in the original study inherently amplifies the likelihood of genetic changes that thereafter lead to the heritability of epigenetic changes. We provide evidence that genetic changes from multiple sources do indeed occur in these experiments and explore several avenues by which these changes could be causal to the apparent inheritance of epigenetic changes. We conclude a genetic basis of inheritance cannot be ruled out and thus transgenerational epigenetic inheritance has not been adequately established by the original study.
    MeSH term(s) Mice ; Animals ; DNA Methylation ; Epigenesis, Genetic ; Mammals/genetics ; Inheritance Patterns ; Epigenomics
    Language English
    Publishing date 2024-02-18
    Publishing country United States
    Document type Journal Article
    ISSN 1559-2308
    ISSN (online) 1559-2308
    DOI 10.1080/15592294.2024.2318519
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  3. Article: Perinatal stress and epigenetics.

    Szyf, Moshe

    Handbook of clinical neurology

    2021  Volume 180, Page(s) 125–148

    Abstract: Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and ... ...

    Abstract Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and regulating stress responses throughout the life course. Epigenetic reprogramming in the hippocampus and the hypothalamus play an important role in adapting genome function to experiences and exposures during the perinatal and early life periods and setting up stable phenotypic outcomes. Epigenetic programming during development enables one genome to express multiple cell type identities. The most proximal epigenetic mark to DNA is a covalent modification of the DNA itself by enzymatic addition of methyl moieties. Cell-type-specific DNA methylation profiles are generated during gestational development and define cell and tissue specific phenotypes. Programming of neuronal phenotypes and sex differences in the hypothalamus is achieved by developmentally timed rearrangement of DNA methylation profiles. Similarly, other stations in the life trajectory such as puberty and aging involve predictable and scheduled reorganization of DNA methylation profiles. DNA methylation and other epigenetic marks are critical for maintaining cell-type identity in the brain, across the body, and throughout life. Data that have emerged in the last 15 years suggest that like its role in defining cell-specific phenotype during development, DNA methylation might be involved in defining experiential identities, programming similar genes to perform differently in response to diverse experiential histories. Early life stress impact on lifelong phenotypes is proposed to be mediated by DNA methylation and other epigenetic marks. Epigenetic marks, as opposed to genetic mutations, are reversible by either pharmacological or behavioral strategies and therefore offer the potential for reversing or preventing disease including behavioral and mental health disorders. This chapter discusses data testing the hypothesis that DNA methylation modulations of the HPA axis mediate the impact of early life stress on lifelong behavioral and physical phenotypes.
    MeSH term(s) Animals ; DNA Methylation/genetics ; Epigenesis, Genetic ; Female ; Humans ; Hypothalamo-Hypophyseal System ; Male ; Phenotype ; Pituitary-Adrenal System ; Pregnancy ; Stress, Psychological/genetics
    Language English
    Publishing date 2021-07-05
    Publishing country Netherlands
    Document type Journal Article ; Review
    ISSN 0072-9752
    ISSN 0072-9752
    DOI 10.1016/B978-0-12-820107-7.00008-2
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  4. Article ; Online: The epigenetics of perinatal stress
.

    Szyf, Moshe

    Dialogues in clinical neuroscience

    2020  Volume 21, Issue 4, Page(s) 369–378

    Abstract: Early life adversity is associated with long-term effects on physical and mental health later in life, but the mechanisms are yet unclear. Epigenetic mechanisms program cell-type-specific gene expression during development, enabling one genome to be ... ...

    Abstract Early life adversity is associated with long-term effects on physical and mental health later in life, but the mechanisms are yet unclear. Epigenetic mechanisms program cell-type-specific gene expression during development, enabling one genome to be programmed in many ways, resulting in diverse stable profiles of gene expression in different cells and organs in the body. DNA methylation, an enzymatic covalent modification of DNA, has been one of the principal epigenetic mechanisms investigated. Emerging evidence is consistent with the idea that epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Whereas there is evidence supporting this hypothesis in animal studies, human studies have been less conclusive. A major problem is the fact that the brain is inaccessible to epigenetic studies in humans and the relevance of DNA methylation in peripheral tissues to behavioral phenotypes has been questioned. In addition, human studies are usually confounded with genetic and environmental heterogeneity and it is very difficult to derive causality. The idea that epigenetic mechanisms mediate the life-long effects of perinatal adversity has attractive potential implications for early detection, prevention, and intervention in mental health disorders will be discussed.
.
    MeSH term(s) Animals ; DNA Methylation/physiology ; Epigenesis, Genetic/genetics ; Epigenomics/methods ; Humans ; Mental Disorders/genetics ; Mothers/psychology ; Stress, Psychological/genetics
    Language English
    Publishing date 2020-01-13
    Publishing country France
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2188781-0
    ISSN 1958-5969 ; 1294-8322
    ISSN (online) 1958-5969
    ISSN 1294-8322
    DOI 10.31887/DCNS.2019.21.4/mszyf
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6188: Show issues Location:
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  5. Article: Increasing Specificity of Targeted DNA Methylation Editing by Non-Enzymatic CRISPR/dCas9-Based Steric Hindrance.

    Sapozhnikov, Daniel M / Szyf, Moshe

    Biomedicines

    2023  Volume 11, Issue 5

    Abstract: As advances in genome engineering inch the technology towards wider clinical use-slowed by technical and ethical hurdles-a newer offshoot, termed "epigenome engineering", offers the ability to correct disease-causing changes in the DNA without changing ... ...

    Abstract As advances in genome engineering inch the technology towards wider clinical use-slowed by technical and ethical hurdles-a newer offshoot, termed "epigenome engineering", offers the ability to correct disease-causing changes in the DNA without changing its sequence and, thus, without some of the unfavorable correlates of doing so. In this review, we note some of the shortcomings of epigenetic editing technology-specifically the risks involved in the introduction of epigenetic enzymes-and highlight an alternative epigenetic editing strategy using physical occlusion to modify epigenetic marks at target sites without a requirement for any epigenetic enzyme. This may prove to be a safer alternative for more specific epigenetic editing.
    Language English
    Publishing date 2023-04-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines11051238
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  6. Article ; Online: The PROTECTOR strategy employs dCas orthologs to sterically shield off-target sites from CRISPR/Cas activity.

    Sapozhnikov, Daniel M / Szyf, Moshe

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 2280

    Abstract: Off-target mutagenesis of CRISPR/Cas systems must be solved to facilitate safe gene therapy. Here, we report a novel approach, termed "PROTECTOR", to shield known off-target sites by directing the binding of an orthologous nuclease-dead Cas protein to ... ...

    Abstract Off-target mutagenesis of CRISPR/Cas systems must be solved to facilitate safe gene therapy. Here, we report a novel approach, termed "PROTECTOR", to shield known off-target sites by directing the binding of an orthologous nuclease-dead Cas protein to the off-target site to sterically interfere with Cas activity. We show that this method reduces off-target mutation rates of two well-studied guide RNAs without compromising on-target activity and that it can be used in combination with high-fidelity Cas enzymes to further reduce off-target editing. This expands the suite of off-target mitigation strategies and offers an ability to protect off-target sites even when their sequences are fully identical to target sites.
    MeSH term(s) CRISPR-Cas Systems ; Mutagenesis ; Gene Editing/methods
    Language English
    Publishing date 2023-02-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-29332-2
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  7. Article ; Online: The PROTECTOR strategy employs dCas orthologs to sterically shield off-target sites from CRISPR/Cas activity

    Daniel M. Sapozhnikov / Moshe Szyf

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 12

    Abstract: Abstract Off-target mutagenesis of CRISPR/Cas systems must be solved to facilitate safe gene therapy. Here, we report a novel approach, termed "PROTECTOR", to shield known off-target sites by directing the binding of an orthologous nuclease-dead Cas ... ...

    Abstract Abstract Off-target mutagenesis of CRISPR/Cas systems must be solved to facilitate safe gene therapy. Here, we report a novel approach, termed "PROTECTOR", to shield known off-target sites by directing the binding of an orthologous nuclease-dead Cas protein to the off-target site to sterically interfere with Cas activity. We show that this method reduces off-target mutation rates of two well-studied guide RNAs without compromising on-target activity and that it can be used in combination with high-fidelity Cas enzymes to further reduce off-target editing. This expands the suite of off-target mitigation strategies and offers an ability to protect off-target sites even when their sequences are fully identical to target sites.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Methyl-CpG binding domain protein 2 (Mbd2) drives breast cancer progression through the modulation of epithelial-to-mesenchymal transition.

    Mahmood, Niaz / Arakelian, Ani / Szyf, Moshe / Rabbani, Shafaat A

    Experimental & molecular medicine

    2024  Volume 56, Issue 4, Page(s) 959–974

    Abstract: Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been implicated in different types of malignancies, including breast cancer. However, the exact role of Mbd2 in various stages of breast cancer growth and progression in vivo ... ...

    Abstract Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been implicated in different types of malignancies, including breast cancer. However, the exact role of Mbd2 in various stages of breast cancer growth and progression in vivo has not been determined. To test whether Mbd2 plays a causal role in mammary tumor growth and metastasis, we performed genetic knockout (KO) of Mbd2 in MMTV-PyMT transgenic mice and compared mammary tumor progression kinetics between the wild-type (PyMT-Mbd2
    MeSH term(s) Animals ; Female ; Humans ; Mice ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; DNA Methylation ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Mice, Knockout ; Mice, Transgenic ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction
    Chemical Substances DNA-Binding Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Mbd2 protein, mouse
    Language English
    Publishing date 2024-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1328915-9
    ISSN 2092-6413 ; 1226-3613 ; 0378-8512
    ISSN (online) 2092-6413
    ISSN 1226-3613 ; 0378-8512
    DOI 10.1038/s12276-024-01205-2
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4775: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  9. Article ; Online: Prospects for Medications to Reverse Causative Epigenetic Processes in Neuropsychiatry Disorders.

    Szyf, Moshe

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2017  Volume 42, Issue 1, Page(s) 367–368

    Language English
    Publishing date 2017
    Publishing country England
    Document type Journal Article
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/npp.2016.219
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2379: Show issues Location:
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  10. Article ; Online: Enzyme-free targeted DNA demethylation using CRISPR-dCas9-based steric hindrance to identify DNA methylation marks causal to altered gene expression.

    Sapozhnikov, Daniel M / Szyf, Moshe

    Nature protocols

    2022  Volume 17, Issue 12, Page(s) 2840–2881

    Abstract: DNA methylation involves the enzymatic addition of a methyl group primarily to cytosine residues in DNA. This protocol describes how to produce complete and minimally confounded DNA demethylation of specific sites in the genome of cultured cells by ... ...

    Abstract DNA methylation involves the enzymatic addition of a methyl group primarily to cytosine residues in DNA. This protocol describes how to produce complete and minimally confounded DNA demethylation of specific sites in the genome of cultured cells by clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and without the involvement of an epigenetic-modifying enzyme, the purpose of which is the evaluation of the functional (i.e., gene expression or phenotypic) consequences of DNA demethylation of specific sites that have been previously implicated in particular pathological or physiological contexts. This protocol maximizes the ability of the easily reprogrammable CRISPR-dCas9 system to assess the impact of DNA methylation from a causal rather than correlational perspective: alternative protocols for CRISPR-dCas9-based site-specific DNA methylation or demethylation rely on the recruitment of epigenetic enzymes that exhibit additional nonspecific activities at both the targeted site and throughout the genome, confounding conclusions of causality of DNA methylation. Inhibition or loss of DNA methylation is accomplished by three consecutive lentiviral transductions. The first two lentiviruses establish stable expression of dCas9 and a guide RNA, which will physically obstruct either maintenance or de novo DNA methyltransferase activity at the guide RNA target site. A third lentivirus introduces Cre recombinase to delete the dCas9 transgene, which leads to loss of dCas9 from the target site, allowing transcription factors and/or the transcription machinery to interact with the demethylated target site. This protocol requires 3-8 months to complete owing to prolonged cell passaging times, but there is little hands-on time, and no specific skills beyond basic molecular biology techniques are necessary.
    MeSH term(s) Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; RNA, Guide, CRISPR-Cas Systems/genetics ; DNA Methylation ; Gene Editing/methods ; CRISPR-Cas Systems/genetics ; DNA Demethylation ; Gene Expression
    Chemical Substances RNA, Guide, CRISPR-Cas Systems
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-022-00741-3
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