In search of lost time: Enhancers as modulators of timing in lymphocyte development and differentiation

Abstract Proper timing of gene expression is central to lymphocyte development and differentiation. Lymphocytes often delay gene activation for hours to days after the onset of signaling components, which act on the order of seconds to minutes. Such delays play a prominent role during the intricate choreography of developmental events and during the execution of an effector response. Though a number of mechanisms are sufficient to explain timing at short timescales, it is not known how timing delays are implemented over long timescales that may span several cell generations. Based on the literature, we propose that a class of cis ‐regulatory elements, termed “timing enhancers,” may explain how timing delays are controlled over these long timescales. By considering chromatin as a kinetic barrier to state switching, the timing enhancer model explains experimentally observed dynamics of gene expression where other models fall short. In this review, we elaborate on features of the timing enhancer model and discuss the evidence for its generality throughout development and differentiation. We then discuss potential molecular mechanisms underlying timing enhancer function. Finally, we explore recent evidence drawing connections between timing enhancers and genetic risk for immunopathology. We argue that the timing enhancer model is a useful framework for understanding how cis‐ regulatory elements control the central dimension of timing in lymphocyte biology.