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A study by the Nerlov group, published in Nature Cell Biology last month, has shown an important role of epigenetic programming in determining which cell types haematopoietic stem cells generate, and also how quickly this happens.
Epigenetics
Epigenetics is the study of how the genome controls the expression of genes without changing the DNA sequence. For example, DNA can be packed more tightly into chromatin (the mix of DNA and proteins that makes up chromosomes), making genes in that part of the genome less accessible and therefore reducing their expression levels.
Haematopoietic stem cells
Haematopoietic stem cells (HSCs) are rare cells that reside in the bone marrow and can self-renew and regenerate while producing sub-types of blood cells, such as lymphocytes and platelets. This process of differentiation is known as haematopoiesis. Even though HSCs are multipotent, individual HSCs have been identified that only produce a subset of blood cell types. This is called HSC fate restriction.
Investigating HSC fate restriction
So far, it is not understood how, or why, HSC fate restriction happens. Investigating this can be challenging as it is difficult to isolate the different HSC sub-types at sufficient purity for accurate characterisation.
A new study, published by Yiran Meng et al., investigated HSC differentiation pathways and the priming mechanisms of HSC subtypes with different fate restrictions. The methods they used included generating fate-restricted HSC clones by single-cell transplantation into mice, RNA-seq to analyse gene transcription (DNA being copied into RNA), and ATAC-seq to measure chromatin accessibility.
In this study, the research team (which included researchers from the MRC Molecular Haematology Unit) were able to demonstrate for the first time that HSCs generate platelets with different kinetics and that lymphocyte production by HSCs is epigenetically programmed.
Platelet production
One HSC subtype is exclusively involved in platelet production, which has previously been shown to occur via both a canonical pathway and a direct pathway, the latter involving fewer intermediate steps. The authors found that the direct pathway originates from platelet-restricted HSCs, and produces platelets faster, but generates fewer, than the canonical pathway.
The accelerated differentiation of platelet-restricted HSCs was paralleled by both increased accessibility of platelet-specific chromatin and higher expression of platelet-specific genes. Platelet-restricted HSCs are therefore molecularly primed for rapid development into platelets.
Lymphocyte production
The researchers also found that although the HSCs that generate lymphocytes did not show active expression of lymphoid-specific genes, they did show higher chromatin accessibility of lymphoid-specific enhancers. This provides the cells with a ‘latent memory’ of what they may become once they differentiate. Runx3 was a key transcription factor that bound to lymphoid enhancers in lymphocyte-producing HSCs. Furthermore, aged HSCs, which make lymphocytes only poorly, expressed low levels of Runx3 and restoring Runx3 expression in these HSCs re-opened their lymphoid enhancers. This highlighted the importance of epigenetic programming in both HSC fate restriction and ageing.
Senior author Claus Nerlov said “We now have a better understanding of how different stem cells are generated and how they are affected by ageing – this provides new strategies for how to improve blood cell production, and the immune response in particular, in older individuals.
Read the full article here: https://www.nature.com/articles/s41556-023-01137-5#Sec1