Chromatin priming elements establish immunological memory in T cells without activating transcription

Abstract

We have identified a simple epigenetic mechanism underlying the establishment and maintenance of immunological memory in T cells. By studying the transcriptional regulation of inducible genes we found that a single cycle of activation of inducible factors is sufficient to initiate stable binding of pre-existing transcription factors to thousands of newly activated distal regulatory elements within inducible genes. These events lead to the creation of islands of active chromatin encompassing nearby enhancers, thereby supporting the accelerated activation of inducible genes, without changing steady state levels of transcription in memory T cells. These studies also highlighted the need for more sophisticated definitions of gene regulatory elements. The chromatin priming elements defined here are distinct from classical enhancers because they function by maintaining chromatin accessibility rather than directly activating transcription. We propose that these priming elements are members of a wider class of genomic elements that support correct developmentally regulated gene expression.

T Cell Receptor and Cytokine Signaling Can Function at Different Stages to Establish and Maintain Transcriptional Memory and Enable T Helper Cell Differentiation

“…By identifying all of the DHSs that are present in recently activated murine CD4 T blast cells and CD4 memory T cells, but not in naïve CD4 T cells, we identified ~3,000 newly acquired and stably maintained primed DHSs (pDHSs) that could potentially account for immunological memory in T cells (Figures 3A,B) (10). These DHSs fulfilled some of the essential features needed for a priming mechanism, because they supported the maintenance of domains of active chromatin modified by H3K4me2 and H3K27ac without having any significant impact on steady-state levels of transcription (10, 18) (Figure 3B). Consistent with this, transcriptional memory has been associated with a retention of H3K4me2 in other systems (27, 65).…”

“…Conversely, IL-4 and STAT6 signaling in CD4 T cells triggers differentiation into type 2 helper (Th2) cells expressing TCR-inducible genes such as IL4 which are activated by the TF GATA3. Recently activated T blast cells and differentiated T cells remain tightly regulated and rely on ongoing activation of TCR signaling to express inducible immune response genes (18). …”

“…The process of T blast cell transformation, which is required to make the rapid recall response possible, involves extensive chromatin remodeling, whereby the Brg1 SWI/SNF family chromatin remodeling complex mediates epigenetic reprogramming of the genome to prime inducible loci for transcriptional reactivation (24). This hit-and-run mechanism, triggered by TCR signaling, establishes thousands of open chromatin regions embedded within extensive active chromatin domains (10, 18). Once formed, these primed regions are stably maintained by mechanisms independent of TCR signaling.…”

“…However, in addition to differentiation-specific DHSs, CD4 T cells acquire many DHSs in genes such as IL4 in recently activated T cells prior to terminal differentiation (10, 42). These newly acquired DHSs represent the early stages of acquiring transcriptional competency prior to the activation of active transcription (18, 23, 45). …”

“…It is also established that activated T cells induce cytokine or chemokine production by virtue of enhanced TCR signaling (11, 12), loss of repressive chromatin modifications (13–15), increased mRNA stability (16), and more efficient translation of cytokine mRNAs (17). However, some of these mechanisms are only relevant for a subset of immune response genes (18), whereas active chromatin modifications represent a more universal mechanism of maintaining immunological memory throughout the T cell compartment (10). In this review, we will focus on just the role of active chromatin priming in T cells and present some new analyses of previously published data to illustrate the potential of TCR-inducible chromatin priming in underpinning the subsequent stages of T cell differentiation.…”