The role of human CBX proteins in human benign and malignant hematopoiesis

Johannes Jung

    Research output: ThesisThesis fully internal (DIV)

    350 Downloads (Pure)

    Abstract

    Polycomb Proteins are chromatin-associated proteins, which assemble in multimeric protein complexes to regulate transcription of genes through post-translational modifications of histone tails.
    In this PhD project, we studied the role of human Polycomb CBX proteins in the regulation of human hematopoietic stem and progenitor cells by enforced retroviral overexpression.
    We demonstrate that among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem- and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in AML, and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation.
    To further unravel the molecular mechanism by which CBX7 exerts its potent activity and taking into account that PcG proteins are known to operate in large protein complexes we performed mass-spectrometry to identify novel interactions partners. So far, the role of CBX proteins was limited to an epigenetic reader of trimethylated lysines on histone 3.
    Mass spectrometry analysis revealed novel non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1 and EHMT1 and -2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover novel, non-canonical crosstalk between epigenetic pathways revealing new therapeutic opportunities for leukemia.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • de Haan, Gerald, Supervisor
    • Bystrykh, Lenja, Co-supervisor
    • Huls, Gerwin, Assessment committee
    • Gil, J., Assessment committee, External person
    • Lengerke, C., Assessment committee, External person
    Award date17-Sep-2018
    Place of Publication[Groningen]
    Publisher
    Print ISBNs9789403409054
    Publication statusPublished - 2018

    Cite this