Tunable, division-independent control of gene activation timing by a polycomb switch
Nicholas A. Pease,
Phuc H.B. Nguyen,
Marcus A. Woodworth,
Kenneth K.H. Ng,
Blythe Irwin,
Joshua C. Vaughan,
Hao Yuan Kueh
Affiliations
Nicholas A. Pease
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA
Phuc H.B. Nguyen
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA
Marcus A. Woodworth
Biological Physics, Structure and Design Program, University of Washington, Seattle, WA 98195, USA; Department of Chemistry, University of Washington, Seattle, WA 98195, USA
Kenneth K.H. Ng
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
Blythe Irwin
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
Joshua C. Vaughan
Department of Chemistry, University of Washington, Seattle, WA 98195, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA
Hao Yuan Kueh
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Corresponding author
Summary: During 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.
