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  2. Targeting SIRT4/TET2 signaling alleviates human keratinocyte senescence by reducing 5-hmC loss

Targeting SIRT4/TET2 signaling alleviates human keratinocyte senescence by reducing 5-hmC loss

  • Lab Invest. 2023 Oct 26:100268. doi: 10.1016/j.labinv.2023.100268.
Yi Yi 1 Yuchang Wang 2 Yiping Wu 1 Yukun Liu 3
Affiliations

Affiliations

  • 1 Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China.
  • 2 Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China. Electronic address: annine.liu1989@gmail.com.
Abstract

Skin aging is characterized by wrinkle formation and increased frailty and laxity, leading to the risk of age-related skin disease. The keratinocyte is an important component of the epidermis in skin structure, and keratinocyte senescence has been identified as a pivotal factor in skin aging development. Because epigenetic pathways play a vital role in the regulation of skin aging, we evaluated human skin samples for DNA hydroxymethylation (5-hydroxymethylcytosine; 5-hmC) and SIRT4 expression. Results found that both 5-hmC and SIRT4 showed a significant decrease in aged human skin samples. To test the results in vitro, human keratinocytes were cultured in H2O2, which modulates skin aging in vivo. H2O2-induced keratinocytes showed senescence-associated protein expression as well as significant downregulation of 5-hmC and SIRT4 expression. Moreover, 5-hmC converting Enzymes ten-eleven translocation 2 (TET2) showed a decrease as well as enhanced TET2 acetylation level in H2O2-induced keratinocytes. However, the overexpression of SIRT4 in keratinocyte alleviate the senescence phenotype such as senescence-associated protein expression as well as decrease the TET2 acetylation but increase TET2 and 5-hmC expression. Our results provide a novel relevant mechanism whereby epigenetic regulation of keratinocytes in skin aging may be correlated with SIRT4 expression and TET2 acetylation in 5-hmC alteration. Our study may provide a potential strategy for anti-skin aging, which targets the SIRT4/TET2 axis involving epigenetic modification in keratinocyte senescence.

Keywords

5-hmC; DNA hydroxymethylation; Epigenetic modification; SIRT4; Skin aging; TET2.

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