DNAmethylation is highly involved in the lineage commitment of HSCs into eithermyeloid or lymphoid progenitors, although commitment to the myeloid lineimplicates lesser global DNA methylation levels as compared to the lymphoidline (Ji et al., 2010). As evidenced by Ji and colleagues, HSCs treated with aDnmt inhibitor led to a functional commitment bias towards the myeloid line.

Additionally, murine HSCs with hypomorphic Dnmt1 activity are unable to repressessential myeloerythoid regulatory genes and similarly displays skeweddifferentiation towards the myeloid line . The data, therefore, suggest that unlessprecise DNA methylation-mediated suppression of key myeloerythoid regulatorygenes are present for commitment to the lymphoid line, the ‘standard’haematopoietic commitment is towards the myeloid line . Moreover, via a competitive repopulation assay,transplanted Dnmt1-conditional KO HSCs were unable to self-renew efficiently ascompared to the wild-type (WT), indicating the essential role of Dnmt1 inself-renewal as well. Incomparison, Dnmt3A-deficient HSCs and to a lower degree, Dnmt3B-deficient HSCsdisplay a differentiation impairment in-vivoafter a prolonged proliferation period, characterized by Dnmt3A-deficient HSCswith significantly elevated self-renewal rates as compared to the WT.Accordingly, the skewed commitment towards self-renewal instead ofdifferentiation, and expansion of the HSC pool in Dnmt3A-deficient HSCs arelargely due to hypomethylation and therefore increased transcription of HSCmultipotency genes, for example, Runx1and Gata3  Notably, Tet2 ablation in HSCs results in commitment bias to differentiatetowards the myeloid line and increased self-renewal rates, resembling thedefective phenotypes of Dnmt1 loss and de-novo DNA methyltransferases-deficiency . Thus, it appears that the precise coordination and regulation ofDNA methylation and hydroxymethylation functions in tandem to prevent aberrantgene expression and promote normal HSC activity.

However, aberrant methylation of enhancer regions is highly associatedwith leukaemias, where a recent study observed that Dnmt3A-deficiency lead tohypomethylation of enhancer regions associated with normal hematopoieticfunction and that Dnmt3A loss in HSCs is usually the permissive factor forsecondary hits to occur, actingas a possible tumor suppressor in haematological malignancies .


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