KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Zhang, Boyi; Long, Qilai; Wu, Shanshan; Song, Shuling; Xu, Qixia; Liu, Han; Qian, Min; Ren, Xiaohui; Jiang, Jing; Fu, Qiang; Guo, Jianming; Zhang, Xiaoling; Chang, Xing; Lam, Eric; Campisi, Judith; Kirkland, James L.; Sun, Yu

doi:10.1101/2020.08.03.235465

Cited by 7 publications

(8 citation statements)

References 79 publications

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“…1F, 2G). When we treated cells on a 2D stiff substate with a KDM4 inhibitor, ML324 44 , during the expansion process, we found that chromatin architecture (H3K9me3 foci, nuclear area) changed significantly in comparison to the vehicle control (DMSO) cells (Fig. 4B,C,D), yet the nuclear aspect ratio did not change significantly compared to DMSO controls (Fig.…”

Section: Demethylase Inhibition Partially Restores Both Chondrogenic H3k9me3 Chromatin Architecture and Gene Expression Following Expansimentioning

confidence: 96%

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Scott

Casas

Schneider

et al. 2021

Preprint

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Understanding how cells remember previous mechanical environments to influence their fate, or mechanical memory, informs the design of biomaterials and therapies in medicine. Current regeneration therapies require two-dimensional (2D) cell expansion processes to achieve large cell populations critical for the repair of damaged (e.g. connective and musculoskeletal) tissues. However, the influence of mechanical memory on cell fate following expansion is unknown, and mechanisms defining how physical environments influence the therapeutic potential of cells remain poorly understood. Here, we show that the organization of histone H3 trimethylated at lysine 9 (H3K9me3) and expression of tissue-identifying genes in primary cartilage cells (chondrocytes) transferred to three-dimensional (3D) hydrogels depends on the number of previous population doublings on tissue culture plastic during 2D cell expansion. Decreased levels of H3K9me3 occupying promoters of dedifferentiation genes after the 2D culture were also retained in 3D culture. Suppression of H3K9me3 during expansion of cells isolated from a murine model similarly resulted in the loss of the chondrocyte phenotype and global remodeling of nuclear architecture. In contrast, increasing levels of H3K9me3 through inhibiting H3K9 demethylases partially rescued the chondrogenic nuclear architecture and gene expression, which has important implications for tissue repair therapies, where expansion of large numbers of phenotypically-suitable cells is required. Overall, our findings indicate mechanical memory in primary cells is encoded in the chromatin architecture, which impacts cell fate and the phenotype of expanded cells.SIGNIFICANCE STATEMENTTissue regeneration procedures, such as cartilage defect repair (e.g. Matrix-induced Autologous Chondrocyte Implantation) often require cell expansion processes to achieve sufficient cells to transplant into an in vivo environment. However, the chondrocyte cell expansion on 2D stiff substrates induces epigenetic changes that persist even when the chondrocytes are transferred to a different (e.g. 3D) or in vivo environment. Treatments to alter epigenetic gene regulation may be a viable strategy to improve existing cartilage defect repair procedures and other tissue engineering procedures that involve cell expansion.

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Section: Demethylase Inhibition Partially Restores Both Chondrogenic H3k9me3 Chromatin Architecture and Gene Expression Following Expansimentioning

confidence: 96%

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Scott

Casas

Schneider

et al. 2021

Preprint

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“…Consistent with the heterogeneity of SCAPs across different senescent cell types, senescent human fat cell progenitors (preadipocytes or mesenchymal stromal cells) are sensitive to D but not Q or F, while senescent human umbilical vein endothelial cells are sensitive to Q or F but not D 14 . Since the first SCAPs were discovered, others have been identified and, based on 31,48,60,63,64,103,157,[214][215][216][217][218] . the various forms of the SASP can comprise chemokines, extracellular matrix proteases, remodeling factors, bioactive lipids, noncoding nucleotides and reactive metabolites 7,31,[59][60][61][62][63][64] .…”

Section: Discovery and Development Of Senolytic Drugsmentioning

confidence: 99%

“…the SASP is a key feature of cellular senescence. Cellular stressors induce DNA damage response signaling, which activates key transcription factors and pathways including NF-κB, CCAAt/enhancer binding protein-β (C/EBPβ), GAtA binding protein 4 (GAtA4), p38 and JAK-StAt, which can drive and modulate the SASP31,48,60,63,64,103,157,[214][215][216][217][218] . the various forms of the SASP can comprise chemokines, extracellular matrix proteases, remodeling factors, bioactive lipids, noncoding nucleotides and reactive metabolites7,31,[59][60][61][62][63][64] .…”

mentioning

confidence: 99%

Cellular senescence and senolytics: the path to the clinic

Chaib

Tchkonia

Kirkland

2022

Nat Med

Self Cite

507

332

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he aging population is steadily increasing. The World Health Organization (WHO) estimates that 1 in 6 people, or 2.1 billion, are expected to be over age 60 by 2030 (ref. 1 ). Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle-and high-income countries [2][3][4][5][6][7] .Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children 6,[8][9][10][11][12] . Indeed, fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome 12,13 . A fundamental aging mechanism that has gained increasing attention is cellular senescence. Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases. After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14 ), promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics, some of which have now been published (Table 1).Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence 3,15 . The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction (including the geriatric syndromes such as frailty, immobility, sarcopenia/ muscle wasting, mild cognitive impairment and incontinence) and loss of resilience (for example, decreased ability to recover from stresses such as injury, surgery, chemotherapy or infections or to mount an antibody response to immunizations) 3,[15][16][17][18] . The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others 6 . For example, interventions that target cellular senescence tend to attenuate other

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“…Given that eliminating senescent cells by senolytics can cause unwanted side effects and that the detrimental effects of senescent cells are largely mediated by the SASP, an alternative approach to targeting senescent cells is to develop senomorphics. Senomorphic drugs, such as BET inhibitor I‐BET‐762 and histone lysine demethylase subfamily 4 (KDM4) inhibitor ML324, aim to suppress the SASP [55,56]. Notably, senomorphics are expected not to affect the arrest of cell growth that is associated with senescence [57].…”

Section: Targeting the Sasp With Senomorphicsmentioning

confidence: 99%

“…Furthermore, inhibition of the epigenetic regulator Bromodomain Containing 4 (BRD4), which helps to organize new super enhancers to drive the SASP, suppresses this secretory phenotype [55]. Similarly, a potent inhibitor that selectively targets KDM4 can also reduce SASP gene expression by altering the accessibility of chromatin and the transcriptomic landscape [56]. Importantly, the inhibition of these chromatin modifiers reduces SASP gene expression without altering the growth arrest of senescent cells, which provides a promising avenue for being targeted in the therapeutic context.…”

Section: Targeting the Sasp With Senomorphicsmentioning

confidence: 99%

Targeting cellular senescence to combat cancer and ageing

2022

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Senescence is a complex cellular process that is implicated in various physiological and pathological processes. It is characterized by a stable state of cell growth arrest and by a secretome of diverse pro‐inflammatory factors, chemokines and growth factors. In this review, we summarize the context‐dependent role of cellular senescence in ageing and in age‐related diseases, such as cancer. We discuss current approaches to targeting senescence to develop therapeutic strategies to combat cancer and to promote healthy ageing, and we outline our vision for future research directions for senescence‐based interventions in these fields.

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KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Cited by 7 publications

References 79 publications

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Cellular senescence and senolytics: the path to the clinic

Targeting cellular senescence to combat cancer and ageing

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