Almars, Amany
(2021)
Heterochromatin protein HP1BP3 modulates haematopoiesis and
leukemogenesis.
PhD thesis, University of Nottingham.
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous malignancy characterized by uncontrolled proliferation of undifferentiated hematopoietic stem/progenitor cells. AML is one of the most comprehensively studied malignancies. Although genetic mutations, particularly chromosomal abnormalities and mutations in known oncogenes, have an integral impact in the development of the disease, increasing evidence suggest the important roles of epigenetic dysregulation on the pathogenesis of AML. Unlike genetic abnormalities, epigenetic alterations are reversible; thus, they can be potential therapeutic targets using specific inhibitors.
The dynamic architecture of chromatin is vital for proper epigenetic response in various cellular events and is maintained by the concerted action of numerous histone and non-histone proteins. Histones undergo different covalent post-translational modifications (PTMs) that take place on the histone tails. Histone PTMs impact the dynamic of the nucleosome, the fundamental unit of chromatin, through wrapping/unwrapping, assembly/disassembly to modulate the chromatin architecture, i.e. conversion from heterochromatin “inactive chromatin” to euchromatin “active chromatin”. PTMs control the interactions between the DNA and the core histones, therefore, the dynamic conversion from heterochromatin to euchromatin influence DNA accessibility, and ultimately regulates cellular processes.
Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) was identified in Dr Nateri’s laboratory as a downstream target of the E3 ubiquitin ligase FBXW7 for degradation. HP1BP3 evolutionarily and structurally belongs to the linker histone H1 family. Moreover, HP1BP3 modulates the entry/exit of nucleosomal DNA by binding to Heterochromatin Protein 1 α (HP1α) and maintains the chromatin integrity during the G1–S phase transition.
However, the roles and mechanism of HP1BP3 action in stem cells and cancers, including haematopoiesis and AML, is largely unknown. Hence in this thesis, we investigated the major role(s) of HP1BP3 underlying the epigenetic reprogramming mechanisms in murine haematopoiesis and AML.
Herein, in brief we demonstrate that:
• HP1BP3 is required for HSC and leukemic self-renewal in vitro, and its reduction (knockdown and knockouts) promotes the myeloid progenitor cells differentiation and apoptosis of AML cells.
• HP1BP3 plays a significant role in hypoxic AML cells in vitro by possibly targeting hypoxia-inducible factors (HIFs).
• Accumulation of HP1BP3 was positively correlated with the
downregulation of H3K9me3 “heterochromatin marker” and
upregulation of H3K9ac “euchromatin marker” while loss of
HP1BP3 induced H3K9me3 levels and decreased H3K9ac.
• HP1BP3 regulates several key genes and miRNAs involved in
proliferation, the cell cycle, proto-oncogenes, tumour suppressor genes and chromatin modifiers identified via sRNA-seq and mRNA-seq transcriptomic analysis and qRT-PCR assays.
Together, our findings reveal a crucial role of HP1BP3 in leukemogenesis, while a further clinical study could identify HP1BP3, an attractive therapeutic target for leukaemia.
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