Lineage decisions of stem and progenitor cells are tightly controlled in time and space to ensure proper development. Cis-acting epigenetic switches can delay the activation of lineage-specifying genes and impact lineage decision making. Here, Hao Yuan Kueh and colleagues study the role of epigenetic timing control in lineage decisions of thymic progenitors in mice, specifically focusing on Bcl11b, a transcription factor that drives T-cell commitment. First, the authors utilise a mouse with a deletion of a distal enhancer involved in delaying Bcl11b activation by days. They observe that the deletion extends the activation delay by ∼3 days but does not affect Bcl11b expression levels or subsequent T-cell development. Delayed Bcl11b activation reduces T-cell output while enhancing the development of type 2 innate lymphoid cells (ILCs) – an alternative lineage option. From single-cell transcriptomic analyses of progenitors at different stages, the authors find that delayed Bcl11b activation prolongs the uncommitted state of progenitors, enabling the upregulation of the pro-ILC transcription factor PLZF. Committed ILC progenitors can activate Bcl11b, but it no longer inhibits ILC fate. Overall, the findings suggest that epigenetic switches can influence the relative timing at which progenitors upregulate Bcl11b and PLZF, which in turn determines progenitor cell fate decisions.
It’s about time: epigenetic switch in T-cell lineage decisions
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It’s about time: epigenetic switch in T-cell lineage decisions. Development 1 December 2024; 151 (23): e151_e2303. doi:
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