1. Tunable, division-independent control of gene activation timing by a polycomb switch.
- Author
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Pease NA, Nguyen PHB, Woodworth MA, Ng KKH, Irwin B, Vaughan JC, and Kueh HY
- Subjects
- Animals, Cell Lineage genetics, Epigenesis, Genetic, Genetic Loci, Histones metabolism, Humans, Lysine metabolism, Methylation, Mice, Inbred C57BL, Protein Conformation, Repressor Proteins chemistry, Repressor Proteins metabolism, T-Lymphocytes cytology, Time Factors, Transcription Factors metabolism, Tumor Suppressor Proteins chemistry, Tumor Suppressor Proteins metabolism, Mice, Cell Division genetics, Polycomb-Group Proteins metabolism, Transcriptional Activation genetics
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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