Directing epigenetic maintenance in normal and malignant haematopoietic stem cells

Background: The process by which stem cell populations are established and maintained and how individual stem cell clones "compete" is a key component to understanding ageing and cancer. Seminal discoveries in a number of tissues have greatly informed our understanding of degenerative diseases and cancer biology in particular. More recently in the blood system, the high prevalence of age-related clonal haematopoiesis in otherwise healthy individuals has demonstrated that aberrations in clonal competition can be a key indicator of early disease development. Most of these mutations are in epigenetic modifiers (e.g., TET2, DNMT3a, ASXL1) which have further been shown to directly regulate proliferation in blood stem cells. Recently we showed that a protein called CIZ1 influences the stability of at least three different histone modifications, such that they are depleted when CIZ1 is not able to form large assemblies inside the nucleus of cells. We think that these assemblies normally form a shield around selected genes and their histones, to protect them from the enzymes that remove the modifications.

Objectives:

Establish the role of CIZ1 in primary HSCs

Understand whether interference with CIZ1 induced shield integrity can destabilize cells in mouse models of malignancy

Novelty and Timeliness

Our analysis of Cip1-interacting Zinc finger protein 1 (CIZ1) has revealed an unexpected role in high-fidelity maintenance of epigenetic landscape, which appears to contribute to disease avoidance. Null cells derived from genetically modified mice remain viable yet prone to instability, while null animals are prone to haematological malignancies. Nothing has been investigated in primary HSCs, the initiating cells of haematological malignancies and this project will combine CIZ1 expertise and HSC biology expertise in the host laboratories. Both labs are currently MRC-funded for related projects that will accelerate the impact of this student project.

Experimental Approach:

The project will involve flow cytometry for isolating and characterising blood cell populations, single cell RNA-sequencing, single cell ATAC-sequencing and functional transplantation assays. These techniques will lead to a comprehensive molecular and cellular understanding of CIZ1-deficient HSCs and its impact on haematopoiesis and disease development.