The m6A writer KIAA1429 regulates photoaging progression via MFAP4-dependent collagen synthesis

Area of Science:

• Epigenetics and RNA modifications
• Dermatology and photoaging research
• Molecular mechanisms of skin aging

Background:

• N6-Methyladenosine (m⁶A) methylation is a crucial RNA modification involved in various biological processes.
• The role of m⁶A methylation in photoaging, particularly UVR-induced skin damage, remains largely unexplored.
• Understanding m⁶A's function in photoaging is vital for developing novel therapeutic strategies.

Purpose of the Study:

• To elucidate the biological role and underlying molecular mechanisms of m⁶A methylation in photoaging.
• To investigate the association between m⁶A levels, specific methylases, and photoaging phenotypes.
• To identify key genes and pathways regulated by m⁶A modification in response to UVR.

Main Methods:

• Detection of m⁶A levels and methylase expression in UVR-induced photoaging models using dot blot, RT-qPCR, western blot, and IHC.
• Global profiling of m⁶A-modified mRNA and total mRNA using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq.
• Investigation of KIAA1429's regulatory mechanism via MeRIP-qPCR, RNA knockdown, and immunofluorescence assays.

Main Results:

• m⁶A levels and KIAA1429 expression were significantly increased in photoaging tissues.
• MeRIP-seq and RNA-seq identified 1331 differentially m⁶A methylated genes, with 90% showing hypermethylation and associated mRNA downregulation.
• KIAA1429 knockdown reversed UVR-induced changes in TGF-bRII and MMP1 expression, and MFAP4 was identified as a direct target, suppressing collagen synthesis.

Conclusions:

• Increased KIAA1429 expression exacerbates photoaging by hindering collagen synthesis through an m⁶A-MFAP4-dependent pathway.
• KIAA1429 emerges as a potential therapeutic target for mitigating UVR-induced photoaging.
• Targeting KIAA1429 could offer a novel strategy for treating skin aging caused by ultraviolet radiation.