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Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts

ABSTRACT: Histone deacetylases (HDACs) are known to be a class of enzymes that remove acetyl groups from lysine chains on histones or other proteins, and play a crucial role in epigenetic regulation and aging process. Previous studies have identified that HDAC4 is down-regulated in aged and UV-irradiated skin in vivo. Therefore, HDAC4 may be an important role in skin aging process. However, the role of HDAC4 in skin aging is rarely known. In this study, we conducted the integrative transcriptome analysis of overexpression and knockdown of HDAC4, and UV- or H2O2-induced senescence in human dermal fibroblast and identified candidate genes which are regulated by HDAC4. Among these genes, DNA damage-inducible transcript 4 (DDIT4) was significantly regulated by HDAC4. We demonstrated that DDIT4 expression was downregulated during senescence and HDAC4 overexpression prevented senescence-induced decrease of DDIT4. In addition, overexpression of DDIT4 reduced SASP and aged-related genes that could promote aging, suggesting that DDIT4 may prevent senescence. Collectively, our results have shown that HDAC4 may play an important role in preventing skin aging by inducing DDIT4 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181329 | GEO | 2021/12/31

REPOSITORIES: GEO

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ANT2 accelerates cutaneous wound healing in aged skin by reverse senescence

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2022-11-21 | GSE206141 | GEO

Downregulation of miR-15b is associated with increased SIRT4 expression in premature senescence and photoaging of the skin

Project description:Sirtuins are deacetylases or ADP-ribosyltransferases which are implicated in multiple pathways involved in metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4, which overexpression negatively impacts on mitochondrial oxidative capacity, with premature senescence and skin aging. Accordingly, SIRT4 mRNA levels were significantly increased in vitro in human dermal fibroblasts after repetitive UVB exposure or in senescence triggered by mitotic spindle stress or ionizing radiation. Similarly, analysis of SIRT4 expression in vivo in human skin revealed upregulation of SIRT4 mRNA levels in the dermal compartment of photaged skin as compared with the dermis of intrinsically aged skin. In all our in vitro models, upregulation of SIRT4 expression was associated with decreased levels of miR-15b. Also, in human skin, highest copy numbers of miR-15b mRNA were detected in the epidermis, and epidermal expression was significantly reduced in photoaged skin as compared with intrinsically aged skin. Reduced miR-15b expression is most likely causally linked to increased SIRT4 expression because we found that (i) miR-15b displays a conserved and direct binding site within the 3'-untranslated region of the SIRT4 gene as demonstrated by luciferase reporter assays and (ii) transfection of oligonucleotides mimicking miR-15b function was sufficient to prevent SIRT4 upregulation in senescent cells in vitro. Thus, we propose that miR-15b acts as a negative regulator of SIRT4 expression to antagonize mitochondrial dysfunction and hence cellular senescence as well as tissue aging, in particular photoaging of the skin.

2016-06-08 | GSE45729 | GEO

Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis

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Molecular Rejuvenation of Gene Expression Pattern of Photoaged and Intrinsically Aged Human Skin by Broadband Light Treatment

Project description:Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply deep sequencing of RNA 3' ends ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging") and the impact of broadband light (BBL) treatment. We find that skin aging was associated with the significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment, i.e. more similar in expression level of youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long non-coding RNAs. Skin aging is not associated with systematic changes in 3' end mRNA processing. Hence, BBL treatment can restore the gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveals a novel set of targets that may lead to new insights into the human skin aging process. Examination of broadband light treated and untreated human skin transcriptomes of 5 women aged 50 years or more. They were compared to the skin transcriptomes of 5 young women aged 30 years or less.

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The comparison of MicroRNA profile of the dermis between young and old human

2016-02-05 | GSE72264 | GEO

Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis (ChIP-Seq)

Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1gamma Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.

2018-04-17 | GSE113181 | GEO

Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis (miRNA-Seq)

Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.

2018-06-30 | GSE116303 | GEO

Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis

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