The highly structured and hierarchical haematopoietic system is defined by the existence of a pool of haematopoietic stem cells (HSCs) at the apex, which possess both multipotent differentiation and self-renewal properties. The HSC pool is heterogenous in terms of self-renewal and differentiation capacity, and HSCs with various genetic alterations lie intermingled with wild type (WT) HSCs. Clonal expansion of HSCs is an ineluctable feature of advancing age, and age related clonal haematopoiesis (ARCH) is associated with an increased risk of haematological malignancy, atherosclerosis and cardiovascular disease. The functional effects of these clonal expansions remain to be thoroughly investigated in primary human HSCs. In this thesis, I have focused on 2 methyltransferase genes, PRMT5 and DNMT3A, which are both epigenetic modulators of HSC function. Pharmacological inhibition of PRMT5 in healthy human cord blood (hCB) haematopoietic stem and progenitor cells (HSPCs) leads to reduced HSPC proliferation and a relative differentiation block at the CD34+ progenitor level in a dose dependent manner. While PRMT5 has been identified by others as an important therapeutic target in the context of haematological malignancies, my work indicates its clinical applicability may be limited by the likely toxicity of PRMT5 inhibition on HSPCs, which could lead to significant myelosuppression. Mutations in the gene DNMT3A are the most common in ARCH and are associated with haematological and non-haematological diseases with significant morbidity and mortality. The R882 mutation is the most common within DNMT3A, especially in the context of haematological disease. I used single cell biology tools to obtain functional data from 12 primary human samples from ARCH individuals and acute myeloid leukaemia (AML) patients. A total of 2990 single HSC/multi-potent progenitor (MPP) derived colonies from DNMT3A mutant HSCs/MPPs and internal WT control HSC/MPPs from within each individual were compared. DNMT3A R882 mutation confers an intrinsic differentiation phenotype, with DNMT3A R882 mutant HSC/MPPs displaying more efficient differentiation towards neutrophils and less efficient monocyte differentiation in vitro compared to internal WT control HSC/MPPs in 6 independent individuals. No overall lineage bias is observed in DNMT3A R882 mutant HSC/MPPs, and no selective differentiation advantage. RNA sequencing of single HSC/MPP derived colonies containing mature monocytes confirmed that DNMT3A R882 mutant HSC/MPPs produce less mature monocytes, and are marked by upregulation of metabolic and inflammatory gene pathways. Overall, these functional phenotypes provide critical insight into the inherent functional effects of DNMT3A R882 mutation at the HSC/MPP level in humans, beyond the previously described transcriptional priming towards more quiescent HSCs and increased self-renewal phenotypes. Further mechanistic understanding will be required to elucidate the link between the myeloid differentiation phenotypes observed in my study and the inflammatory conditions associated with ARCH.