Stage-specific epigenetic gene silencing during thymocyte lineage commitment

Abstract

During lineage commitment, precursor cells must establish their signature gene expression programs to endow them with the requisite set of cellular functions. To maintain cellular identity, the gene expression program must be inherited stably by progeny of lineage-committed cells. Epigenetic regulation serves as a central mechanism to maintain such cellular memory. Although a lot of progress has been made in the last decade towards defining the spectrum of epigenetic modifications on histones and DNA, as well as the relevant enzymatic machinery, the mechanisms by which these modifiers are controlled during development remain poorly understood. Gene regulation at the Cd4 and Thpok loci provides ideal models for developmentally regulated gene silencing. A single transcriptional silencer at each locus establishes heritable, irreversible epigenetic silencing only in lineage-committed cells, whereas the same silencer elements establish a reversible repressive state in precursor cells. The dynamic versus permanent silencing of developmentally regulated loci by the stage-specific functions of silencers will be discussed in the context of cell lineage commitment.