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  1. Article: Identification and characterization of enhancer elements controlling cell type-specific and signalling dependent chromatin programming during hematopoietic development.

    Maytum, Alexander / Edginton-White, Ben / Bonifer, Constanze

    Stem cell investigation

    2023  Volume 10, Page(s) 14

    Abstract: The development of multi-cellular organisms from a single fertilized egg requires to differentially execute the information encoded in our DNA. This complex process is regulated by the interplay of transcription factors with a chromatin environment, both ...

    Abstract The development of multi-cellular organisms from a single fertilized egg requires to differentially execute the information encoded in our DNA. This complex process is regulated by the interplay of transcription factors with a chromatin environment, both of which provide the epigenetic information maintaining cell-type specific gene expression patterns. Moreover, transcription factors and their target genes form vast interacting gene regulatory networks which can be exquisitely stable. However, all developmental processes originate from pluripotent precursor cell types. The production of terminally differentiated cells from such cells, therefore, requires successive changes of cell fates, meaning that genes relevant for the next stage of differentiation must be switched on and genes not relevant anymore must be switched off. The stimulus for the change of cell fate originates from extrinsic signals which set a cascade of intracellular processes in motion that eventually terminate at the genome leading to changes in gene expression and the development of alternate gene regulatory networks. How developmental trajectories are encoded in the genome and how the interplay between intrinsic and extrinsic processes regulates development is one of the major questions in developmental biology. The development of the hematopoietic system has long served as model to understand how changes in gene regulatory networks drive the differentiation of the various blood cell types. In this review, we highlight the main signals and transcription factors and how they are integrated at the level of chromatin programming and gene expression control. We also highlight recent studies identifying the
    Language English
    Publishing date 2023-06-25
    Publishing country China
    Document type Journal Article ; Review
    ZDB-ID 2884645-X
    ISSN 2313-0792 ; 2306-9759
    ISSN (online) 2313-0792
    ISSN 2306-9759
    DOI 10.21037/sci-2023-011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Chromatin priming elements direct tissue-specific gene activity before hematopoietic specification.

    Maytum, Alexander / Edginton-White, Benjamin / Keane, Peter / Cockerill, Peter N / Cazier, Jean-Baptiste / Bonifer, Constanze

    Life science alliance

    2023  Volume 7, Issue 2

    Abstract: Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. ... ...

    Abstract Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications, and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated before the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the up-regulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control.
    MeSH term(s) Chromatin/genetics ; Cell Differentiation/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Transcription Factors/genetics ; Promoter Regions, Genetic/genetics
    Chemical Substances Chromatin ; Transcription Factors
    Language English
    Publishing date 2023-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.202302363
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Impact of Infant Bacille Calmette-Guérin Vaccination on the Immunogenicity of Other Vaccines: A Randomized Exploratory Study.

    Maytum, Alexander / Porter, David / de Whalley, Philip / Thompson, Amber / Plested, Emma / Kerridge, Simon / Liu, Xinxue / Smits, Gaby / van der Klis, Fiona / Snape, Matthew D / Clutterbuck, Elizabeth / Pollard, Andrew J

    The Pediatric infectious disease journal

    2024  

    Abstract: The effect of the Bacille Calmette-Guérin (BCG) vaccine on the immunogenicity of separately administered serogroup C meningococcal vaccine and other vaccinations was examined in 28 infants randomized to receive BCG at age ≤7 days, at 3 months or after ... ...

    Abstract The effect of the Bacille Calmette-Guérin (BCG) vaccine on the immunogenicity of separately administered serogroup C meningococcal vaccine and other vaccinations was examined in 28 infants randomized to receive BCG at age ≤7 days, at 3 months or after study completion. Immunogenicity of the serogroup C meningococcal vaccine and other routine vaccines might be improved when BCG is administered in early infancy.
    Language English
    Publishing date 2024-05-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 392481-6
    ISSN 1532-0987 ; 0891-3668
    ISSN (online) 1532-0987
    ISSN 0891-3668
    DOI 10.1097/INF.0000000000004373
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.

    Coleman, Daniel J L / Keane, Peter / Chin, Paulynn S / Ames, Luke / Kellaway, Sophie / Blair, Helen / Khan, Naeem / Griffin, James / Holmes, Elizabeth / Maytum, Alexander / Potluri, Sandeep / Strate, Lara / Koscielniak, Kinga / Raghavan, Manoj / Bushweller, John / Heidenreich, Olaf / Rabbitts, Terry / Cockerill, Peter N / Bonifer, Constanze

    iScience

    2024  Volume 27, Issue 4, Page(s) 109576

    Abstract: AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and ... ...

    Abstract AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2024.109576
    Database MEDical Literature Analysis and Retrieval System OnLINE

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