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Calcineurin/NFATc1 pathway represses cellular cytotoxicity by modulating histone H3 expression

Yuki Sato1, Makoto Habara1, Shunsuke Hanaki1

  • 1Department of Veterinary Biochemistry, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8511, Japan.

Scientific Reports
|June 26, 2024
PubMed

Insights

Excess histones cause genomic instability. The transcription factor NFATc1 (nuclear factor of activated T cells 1) represses histone gene expression, preventing harmful histone accumulation and maintaining cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Excess histones lead to mitotic chromosome loss and genomic instability, threatening cell survival.
  • Histone degradation in yeast involves the proteasome and Rad53, but transcriptional regulation remains unclear.

Purpose of the Study:

  • To investigate the transcriptional regulation of histone genes.
  • To identify factors controlling histone expression and their role in preventing genomic instability.

Main Methods:

  • Treatment with calcineurin inhibitors.
  • Analysis of transcription factor NFATc1 binding to histone gene promoters.
  • Assessment of histone gene expression in response to intracellular calcium levels.
  • Cell proliferation assays upon histone H3 overexpression.

Main Results:

  • Calcineurin inhibitor treatment elevated histone protein levels.
  • NFATc1 was identified as a repressor of histone transcription, acting downstream of calcineurin.
  • NFATc1 binds to promoters of multiple histone genes.
  • Histone transcription is downregulated by intracellular calcium levels.
  • Overexpression of histone H3 significantly impaired cell proliferation.

Conclusions:

  • NFATc1 plays a crucial role in preventing detrimental histone accumulation.
  • NFATc1 maintains genomic stability by repressing histone gene expression transcriptionally.
  • Intracellular calcium levels modulate histone transcription via NFATc1.
Keywords:
CalcineurinCalciumCancerHistoneNFATcTranscription

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