An epigenomic role of Fe65 in the cellular response to DNA damage

Seungjin Ryu, Francesca Teles, Giuseppina Minopoli, Tommaso Russo, Michael G. Rosenfeld, Yousin Suh

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Previous findings describe Fe65 as a key protein in the cellular response to genotoxic stress. However, the precise molecular mechanism by which Fe65 contributes to DNA damage signaling remains unclear. In this study, we hypothesized that the transcriptional activity of Fe65 may contribute to DNA damage pathways by regulating gene expression patterns activated in response to genotoxic stress. To address this hypothesis, we mapped the global binding profile of Fe65 by chromatin immunoprecipitation (ChIP)-sequencing in the SK-N-SH cells exposed to genotoxic stress. Unexpectedly, the genome-wide location analysis showed a substantial enrichment of Fe65 in the promoter regions of coding genes linked to DNA damage signaling pathways. To further investigate the role of Fe65 in the transcriptional regulation of putative coding target genes identified by ChIP-seq, we performed microarray assays using wild-type (WT) or Fe65 deficient mouse embryonic fibroblasts (MEFs) exposed to oxidative stress with multiple recovery times. Gene ontology analysis of the Fe65-depedent transcriptome suggested that Fe65 modulates the expression of genes critical for DNA damage response. Motif enrichment analysis of regulatory regions occupied by Fe65 revealed a strong correlation with key transcription factors involved in DNA damage signaling pathways, including E2F1, p53, and Jun. Comparison of ChIP-sequencing results with microarray results ultimately identified 248 Fe65-depedent target genes, the majority of which were known regulators of cell cycle, cell death, and DNA replication and repair pathways. We validated the target genes identified by in silico analysis by qPCR experiments. Collectively, our results provide strong evidence that Fe65 plays a role in DNA damage response and cell viability by epigenomic regulation of specific transcriptional programs activated upon genotoxic stress.

Original languageEnglish (US)
Pages (from-to)40-47
Number of pages8
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume776
DOIs
StatePublished - Jun 1 2015

Fingerprint

Epigenomics
DNA Damage
Chromatin Immunoprecipitation
Genes
Gene Expression
Gene Ontology
Nucleic Acid Regulatory Sequences
DNA Replication
Transcriptome
Genetic Promoter Regions
DNA Repair
Computer Simulation
Cell Survival
Cell Cycle
Oxidative Stress
Cell Death
Transcription Factors
Fibroblasts
Genome

Keywords

  • Chromatin immunoprecipitation-sequencing
  • DNA damage response
  • Fe65 transcription
  • Microarray

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

An epigenomic role of Fe65 in the cellular response to DNA damage. / Ryu, Seungjin; Teles, Francesca; Minopoli, Giuseppina; Russo, Tommaso; Rosenfeld, Michael G.; Suh, Yousin.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 776, 01.06.2015, p. 40-47.

Research output: Contribution to journalArticle

Ryu, Seungjin ; Teles, Francesca ; Minopoli, Giuseppina ; Russo, Tommaso ; Rosenfeld, Michael G. ; Suh, Yousin. / An epigenomic role of Fe65 in the cellular response to DNA damage. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2015 ; Vol. 776. pp. 40-47.
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