Chromatin basis of the senescence-associated secretory phenotype

Abstract

Cellular senescence is a stable cell growth arrest. Senescent cells are metabolically active, as exemplified by the secretion of inflammatory cytokines, chemokines, and growth factors, which is termed senescence-associated secretory phenotype (SASP). The SASP exerts a range of functions in both normal health and pathology, which is possibly best characterized in cancers and physical aging. Recent studies demonstrated that chromatin is instrumental in regulating the SASP both through nuclear transcription and via the innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in the cytoplasm. Here, we will review these regulatory mechanisms, with an emphasis on most recent developments in the field. We will highlight the challenges and opportunities in developing intervention approaches, such as targeting chromatin regulatory mechanisms, to alter the SASP as an emerging approach to combat cancers and achieve healthy aging.

Keywords: chromatin structure; cytoplasmic chromatin; enhancer–promoter interaction; senescence-associated secretory phenotype; senomorphics.

Figure 1.. The multifaceted functions of the senescence-associated secretory phenotype (SASP).

The beneficial (in green) and the detrimental (in purple) roles of the SASP are summarized. The specific SASP factors that function in these processes are indicated. Note that the beneficial and detrimental roles played by the specific SASP factors are context-dependent. For instance, IL6 is critical for senescence-associated cellular reprogramming during embryo development, while contributing to the relapse and cancer stemness during therapy-induced senescence.

Figure 2. Key Figure.. Rewiring of promoters, enhancers and promoter-enhancer loops plays a key role in driving the SASP.

Upper left, global remodeling of the enhancer landscape during senescence. Chromatin reader BRD4 is recruited to the newly formed super enhancers marked by H3K27ac to promote the SASP gene expression. Upper right, histone demethylase KDM4 orchestrates the SASP gene transcription by increasing chromatin openness through demethylating H3K9me3 and H3K36me3 at both distal enhancers and promoters of the SASP genes. Lower left, genome-wide redistribution of the METTL3 and METTL14 complex promotes the SASP gene transcription through mediating enhancer-promoter loop formation. Lower right, cohensin redistribution promotes the SASP through specific enhancer-promoter rewiring and chromatin loop reorganization.

Figure 3.. Three dimensional (3D) genomic control of the SASP.

Transcriptionally active and inactive regions of genome form A and B compartments, respectively. Structural maintenance of chromosomes component Condensin II promotes the SASP gene transcription by mediating B-to-A compartmental transition during senescence. Within each compartment, self-interacting domains of genome are organized as topologically associated domains (TADs). Roles of TADs in senescence remain to be fully elucidated. For example, replicative senescence is associated with an increase in short-range intra-TAD interactions, while oncogene-induced senescence is accompanied by a reduction in short-range local intra-TAD interactions. Nuclear HMGB1 regulates the SASP gene transcription by localizing to a subset of TADs boundaries that are enriched in SASP-related genes.

Figure 4.. Cytoplasmic chromatin promotes the SASP through the cGAS-STING innate immune pathway.

Cytoplasmic chromatin fragments (CCF) formation is initiated by dysfunctional mitochondria that produce excessive reactivated oxygen species (ROS). This activates JNK kinase and detachment of DNA damage repair protein 53BP1 from the DNA damage sites. Topoisomerase I (TOP1) forms a TOP1-DNA covalent cleavage complex to enhance cGAS activity to promote the SASP. Upon activation, cGAS catalyzes adenosine 5’-triphosphate (ATP) and guanosine 5’-triphosphate (GTP) into cyclic GMP-AMP (cGAMP) that binds to and activates STING to recruit tank-binding kinase 1 (TBK1). TBK1 phosphorylates NF-κB to drive the expression of its target SASP genes. CCF formation is negatively regulated by nucleases such as lysosomal nuclease DNase II and cytoplasmic exonuclease TREX1. Another source of cytoplasmic DNA that activates the cGAS-STING pathway is originated from RNA polymerase II-mediated transcription of retrotransposons such as Long Interspersed Element 1 (LINE-1 or L1) during senescence. LINE-1 comprises 17% of human genome. LINE-1 encodes two protein products: the RNA binding protein ORF1 and the endonuclease and reverse transcriptase ORF2. Two possible mechanisms may underlie cytoplasmic L1 cDNA accumulation. High levels of L1 mRNA and protein may result in an increase in cytosolic L1 cDNA through reverse transcription. In addition, high levels of cDNA in the nucleus may fail to re-integrate into the genome, which results in its cytosolic localization through an unknown mechanism. However, the mechanisms by which L1 cDNA is generated from the de-repressed L1 remain unknown.

Figure 5.. Leveraging the SASP for cancer therapy.

The SASP plays a context-dependent role in senescence-inducing cancer therapy. Boosting the SASP is known to promote immune surveillance and clearance of senescent cells. In addition, the SASP enhances immune infiltration to synergize with cancer immunotherapy such as immune checkpoint blockades. In contrast, inhibiting the SASP is beneficial in reducing cancer stemness and preventing therapy relapse.