BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance

Abstract

Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

“…Importantly, Brd4 knockdown resulted in a significant decrease in expression of Pd-l1 (Figure 4B), formally demonstrating a functional link between Brd4 and Pd-l1. Analysis of RNA-seq data from a recently published study where BRD4 was depleted using RNAi or inhibited using JQ1 in senescent H-Ras V12 -transformed IMR-90 human fibroblasts confirmed our results in Eμ- Myc lymphomas (Tasdemir et al., 2016). Depletion or inhibition of BRD4 resulted in a significant reduction in CD274 mRNA in the absence of substantive changes in expression of MYC (Figures S3F–S3H).…”

The Chromatin Landscape of Cellular Senescence

“…In particular, increased resolution provided by the latest advances in Hi-C technology and microscopy, such as capture Hi-C [89] and superresolution microscopy [90], will allow us to better understand the relation between changes in chromosome folding and transcriptional activity of individual genes. For example, it was recently reported that in OIS, the enhancer landscape undergoes global remodeling, with recruitment of BRD4 to newly activated super-enhancers proximal to SASP genes [91]. In this case, promoter capture Hi-C [89] could be applied to elucidate the changes in chromosome looping leading to the activation of these enhancers and of their target genes.…”

Targeting Cancer Cells with BET Bromodomain Inhibitors

“…Transgenic Brd4 shRNA mice, in which BRD4 levels are reduced conditionally in adult tissues, show stem cell depletion in the small intestine and hyperplasia of epidermal tissues (Bolden et al 2014). The latter phenotype may reflect the emerging role for BRD4 in tumor suppression, and hence BET inhibition might be expected to worsen certain malignancies (Alsarraj and Hunter 2012; Fernandez et al 2014; Tasdemir et al 2016). Notably, the side effects of BRD4 knockdown in vivo are known to be reversible after restoring BET protein function (Matzuk et al 2012; Bolden et al 2014; Nagarajan et al 2014).…”