Tunable, division-independent control of gene activation timing by a polycomb switch

Cell Rep. 2021 Mar 23;34(12):108888. doi: 10.1016/j.celrep.2021.108888.

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.

Keywords: T cell development; chromatin compaction; epigenetic switch; gene regulation; post-translational histone modifications; stochasticity; timing control; tunability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Division / genetics*
  • Cell Lineage / genetics
  • Epigenesis, Genetic
  • Genetic Loci
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Polycomb-Group Proteins / metabolism*
  • Protein Conformation
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism
  • T-Lymphocytes / cytology
  • Time Factors
  • Transcription Factors / metabolism
  • Transcriptional Activation / genetics*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism

Substances

  • Bcl11b protein, mouse
  • Histones
  • Polycomb-Group Proteins
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Lysine