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Integrated ATAC-Seq and RNA-Seq Identify ATF3 as a Tumor Suppressor in UVB-Induced Keratinocyte Carcinogenesis

Zhi Guo1, Xuyi Deng1, Sheng Lu1

  • 1Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.

Biology
|July 28, 2026
PubMed

Insights

Chronic ultraviolet B (UVB) exposure drives skin cancer by altering gene regulation. We identified ATF3 as a tumor suppressor that, when downregulated, promotes keratinocyte carcinoma via its target gene Guanine deaminase (GDA).

Area of Science:

  • Oncology
  • Dermatology
  • Epigenetics
  • Molecular Biology

Background:

  • Current methods for preventing and treating keratinocyte carcinoma are insufficient.
  • Chronic ultraviolet B (UVB) exposure is a major risk factor, inducing malignant transformation via epigenetic reprogramming.
  • The precise mechanisms of UVB-induced epigenetic changes and their role in skin cancer development require further elucidation.

Purpose of the Study:

  • To investigate the epigenetic and transcriptomic alterations induced by chronic UVB exposure in keratinocytes.
  • To identify novel molecular targets for the intervention of UVB-induced keratinocyte carcinoma.
  • To elucidate the role of the transcription factor ATF3 and its downstream targets in skin cancer progression.

Main Methods:

  • Establishment of a chronic UVB irradiation model in keratinocytes.
  • Integrative analysis using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq).
  • Functional assays and Chromatin Immunoprecipitation quantitative PCR (ChIP-qPCR) to validate gene targets and regulatory interactions.

Main Results:

  • Chronic UVB exposure led to significant changes in chromatin accessibility (4903 differentially accessible regions) and gene expression (1136 differentially expressed genes), with enrichment in inflammatory pathways.
  • Increased accessibility was observed at tumor-promoting gene loci, including TP63, KRT13, KLF8, and EGFR.
  • UVB exposure downregulated the transcription factor ATF3, which was found to repress keratinocyte malignant transformation. Guanine deaminase (GDA) was identified as a direct downstream target of ATF3, with its promoter accessibility and expression upregulated upon ATF3 downregulation, driving malignant progression.

Conclusions:

  • Chronic UVB exposure profoundly remodels the chromatin and transcriptomic landscapes of keratinocytes.
  • The study identifies ATF3 as a critical tumor suppressor in the context of UVB-induced skin cancer.
  • ATF3 and its direct target GDA form a regulatory module that plays a crucial role in suppressing UVB-induced keratinocyte carcinoma.
Keywords:
ATAC-seqATF3RNA-seqchronic UVB radiationkeratinocyte carcinogenesis

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