Abstract
SUMMARYDuring development, progenitors often differentiate many cell generations after receiving signals. These delays must be robust yet tunable for precise population size control. Polycomb repressive mechanisms, involving histone H3 lysine-27 trimethylation (H3K27me3), restrain the expression of lineage-specifying genes in progenitors and may delay their activation and ensuing differentiation. Here, we elucidate an epigenetic switch controlling the T cell commitment gene Bcl11b that holds its locus in a heritable inactive state for multiple cell generations before activation. Integrating experiments and modeling, we identify a mechanism where H3K27me3 levels at Bcl11b, regulated by methyltransferase and demethylase activities, set the time delay at which the locus switches from a compacted, silent state to an extended, active state. This activation delay robustly spans many cell generations, is tunable by chromatin modifiers and transcription factors, and is independent of cell division. With their regulatory flexibility, such timed epigenetic switches may broadly control timing in development.
Highlights
During multicellular development, stem and progenitor cells often differentiate many days and cell divisions after receiving instructive signals
Timing delays in some embryonic systems are generated by mechanisms that count cell divisions (Amodeo et al, 2015; Newport and Kirschner, 1982), differentiation delays during later vertebrate development or in adult stem cells are often uncoupled from cell cycle progression, such that changes to rates of cell division do not affect delay duration (Burton et al, 1999; Gao et al, 1997; Heinzel et al, 2017; Li et al, 2019; Okamoto et al, 2016; Osmond, 1991; Otani et al, 2016)
We investigated the mechanism of a time-delayed epigenetic switch controlling the activation of Bcl11b, a transcription factor essential for T cell lineage commitment and identity (Hosokawa et al, 2018; Ikawa et al, 2010; Li et al, 2010; Figure 1A)
Summary
Stem and progenitor cells often differentiate many days and cell divisions after receiving instructive signals. In classic studies of oligodendrocyte differentiation, precursor cells exposed to signals delayed their differentiation by up to eight cell divisions, due to a cell-autonomous timing mechanism (Gao et al, 1997; Temple and Raff, 1986) Such autonomous timing control is seen in diverse systems, from brain and muscle development to adaptive immunity (Burton et al, 1999; Heinzel et al, 2017; Otani et al, 2016). A mechanism for setting the elapsed time to differentiation apart from cell division could provide functional advantages to cells, including operation in non-dividing cells and an ability to modulate cell expansion while maintaining a constant temporal schedule for differentiation It is unknown how division-independent timing control is implemented on a molecular level
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