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A functional LSD1 coregulator screen reveals a novel transcriptional regulatory cascade connecting R-loop homeostasis

Sabine Pinter1, Franziska Knodel1, Michel Choudalakis1

  • 1Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany.

Nucleic Acids Research
|April 6, 2021
PubMed

Insights

Researchers identified DEAD-box helicase 19A (DDX19A) as a novel regulator of lysine-specific demethylase 1 (LSD1). DDX19A removes R-loops, promoting gene silencing and cellular differentiation, uncovering a new regulatory pathway.

Area of Science:

  • Epigenetics and Gene Regulation
  • Molecular Biology
  • Cancer Biology

Background:

  • Lysine-specific demethylase 1 (LSD1) is crucial for cellular differentiation, regulating gene expression via coregulators.
  • LSD1's role in cancer and its regulatory network are not fully understood.
  • Identifying novel LSD1 coregulators is key to understanding gene regulation and potential therapeutic targets.

Purpose of the Study:

  • To identify novel functional coregulators of LSD1 activity.
  • To elucidate the mechanism by which these coregulators impact gene expression and cellular processes.
  • To investigate the role of identified coregulators in the context of cancer-related gene dysregulation.

Main Methods:

  • Development of a novel fluorescent reporter system to monitor LSD1 activity in real-time.
  • Application of a multiplexed RNA interference (RNAi) screen to identify functional LSD1 coregulators.
  • Biochemical assays to determine binding interactions and functional consequences, including R-loop analysis and chromatin immunoprecipitation.

Main Results:

  • Identification of DEAD-box helicase 19A (DDX19A) as a novel LSD1 coregulator.
  • Suppression of DDX19A leads to increased R-loops and impaired LSD1-mediated gene silencing.
  • DDX19A binds to histone H3K27me3 and removes R-loops, facilitating gene repression via a cascade involving LSD1 and PRC2.

Conclusions:

  • DDX19A acts as a critical regulator in a novel transcriptional cascade controlling gene downregulation.
  • The findings reveal a positive feedback loop involving LSD1, PRC2, and DDX19A for robust gene silencing.
  • This study provides new insights into epigenetic mechanisms underlying cellular differentiation and potential implications for cancer therapy.

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