journal contribution
posted on 2023-04-03, 21:05 authored by Nilgun Tasdemir, Ana Banito, Jae-Seok Roe, Direna Alonso-Curbelo, Matthew Camiolo, Darjus F. Tschaharganeh, Chun-Hao Huang, Ozlem Aksoy, Jessica E. Bolden, Chi-Chao Chen, Myles Fennell, Vishal Thapar, Agustin Chicas, Christopher R. Vakoc, Scott W. Lowe Supplementary Figure S1. Senescence-activated SASP enhancers are marked by H3K4Me1 in proliferating IMR90 cells. Supplementary Figure S2. Reproducibility analyses of biological replicates for H3K27Ac and BRD4 ChIP-Seq. Supplementary Figure S3. Enhancer remodeling during oncogene-induced senescence parallels gene expression changes. Supplementary Figure S4. Genetic and pharmacologic inhibition of BRD4 impairs SASP gene expression during oncogene-induced senescence (OIS). Supplementary Figure S5. BRD4 couples enhancer remodeling to SASP gene expression during etoposide-induced senescence. Supplementary Figure S6. Systemic and cell-autonomous suppression of Brd4 impairs the immune surveillance of senescent hepatocytes.
Funding
NIH
NCI
Lindsay and Goldberg Fellowship from the Watson School of Biological Sciences.
EMBO
Postdoctoral fellowship
Martin Sass Foundation and the Lauri Strauss Leukemia Foundation
Howard Hughes Medical Institute
History
ARTICLE 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.Significance: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612–29. ©2016 AACR.See related commentary by Vizioli and Adams, p. 576.This article is highlighted in the In This Issue feature, p. 561
