Epigenetic blueprint of haematopoietic cells
Epigenetic modifications such as DNA methylation and histone modifications are critical for regulating expression of genes and non-coding RNAs. Haematopoietic stem and progenitor cells (HSPCs) possess the unique capacity for self-renewal and differentiation, giving rise to all the lineages in the blood and immune system. Abnormal arrest at certain stages of development is a sign of neoplastic transformation that can give rise to various haematological cancers such as B cell malignancies, T-lineage acute lymphoblastic leukaemia (T-ALL) or myeloid leukaemia. These are characterised by biological heterogeneity or lack of therapeutic stratification, emphasising the need for novel stage-specific biomarkers for diagnosis or prediction of outcome. The EU-funded BLUEPRINT (A blueprint of haematopoietic epigenomes) project aimed to advance our understanding of how genes are activated or repressed in both healthy and diseased human cells. It brought together 42 academic and industrial participants who utilised state-of-the-art technologies to analyse distinct types of haematopoietic cells. BLUEPRINT has successfully generated and explored the epigenetic mechanisms underlying formation of all blood cell types from HSPCs, progenitors to the mature cell types. Interestingly, they observed that the process of epigenetic programming during monocyte to macrophage differentiation was characterised by epigenetic memory. To better understand the biological and clinical heterogeneity of lymphoid tumours such as precursor B- (preB-), T-ALL and chronic lymphocytic leukaemia (CLL), researchers characterised their epigenome. They found that neoplastic B cells, unlike normal B cells, presented with demethylation of heterochromatin and methylation gain of polycomb-repressed areas. Full epigenomes were also obtained for different subtypes of leukaemia revealing specific epigenetic features. Considerable effort went towards understanding the predisposition to autoimmune diseases like diabetes and inflammatory bowel disease that result from an interplay of genetic and environmental factors. BLUEPRINT discovered that genetic variants were ascribed to specific molecular variations and gene expression alterations. Collectively, BLUEPRINT efforts have successfully mapped the epigenetic landscape in a plethora of haematological conditions. The generated information will fuel drug development efforts, by indicating specific genes and molecular pathways that could be targeted to treat these diseases.
Haematopoietic cells, epigenome, leukaemia, BLUEPRINT, diabetes