Stem cells balance self-renewal with differentiation into mature cells. A fundamental and intriguing question is when during the process of maturation a cell reaches a ‘point of no return’, losing its capacity to self-renew and becoming committed to differentiating into a specific cell type.
Assistant Professor Andres Blanco (University of Pennsylvania), a former post-doc in Ludwig Oxford’s Professor Yang Shi’s laboratory, and colleagues investigated this question in blood stem cells known as haematopoietic myeloid progenitors. In a study published in Cell Reports, they showed that the chromatin environment on DNA - the combination of DNA and histone proteins - plays a key role enforcing cell fate decisions.
The researchers studied the production of terminally differentiated neutrophil white blood cells from myeloid stem cells and found that a combination of remodelling of chromatin structure, activation of gene control elements (enhancers) and changes in transcription factor usage contribute to an irreversible commitment to differentiation. These changes result in reduced accessibility to regulatory DNA sites and disruption of a positive feedback transcription factor activation loop that prevents differentiation.
This greater understanding of the biological mechanisms involved in the production of mature blood cells from blood stem cells could aid strategies to manipulate this process for example, for tissue regeneration or to develop cancer therapies. The new findings have relevance to acute myeloid leukaemia (AML), in which differentiation is arrested. By helping to define the molecular processes involved in differentiation, this study aims to identify targets against which to develop new AML differentiation therapies.