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Updated: Apr 18, 2026

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
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Published on: September 20, 2018

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Altered chromatin accessibility and nucleosome positioning landscape upon HDAC and LSD1 inhibition in cancer cell

Sagnik Sen1, Pierre O Estève1, Devesh Tarasia1

  • 1New England Biolabs Inc, 240 County Road, Ipswich, MA 01938, USA.

Biorxiv : the Preprint Server for Biology
|April 17, 2026
PubMed

Insights

This study reveals how targeting epigenetic enzymes with single or dual inhibitors impacts cancer. A novel platform identified a JunB-mediated mechanism that triggers apoptosis, offering new strategies for combinatorial epigenetic therapy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic enzymes regulate chromatin and contribute to tumor heterogeneity.
  • Targeting these enzymes is a promising cancer therapy strategy, but mono- vs. dual-inhibitor efficacy is unclear.

Purpose of the Study:

  • To compare the efficacy of mono- versus dual-inhibitor strategies targeting epigenetic enzymes.
  • To investigate the molecular mechanisms underlying epigenetic inhibitor responses in cancer.

Main Methods:

  • Developed NicE-viewSeq, a multi-modal platform integrating deep learning-based chromatin accessibility profiling with high-throughput sequencing.
  • Applied epigenetic inhibitors (LSD1, HDACs) and analyzed changes in chromatin landscapes, histone marks, and transcription factor binding.

Main Results:

  • Inhibition of LSD1 or HDACs alone or together altered accessible chromatin and nucleosome positioning.
  • Coordinated modulation of histone marks and the CoREST complex was observed.
  • Identified ETS, RUNT, and bZIP transcription factors with enhanced chromatin association; uncovered a CoREST-RUNX-JunB axis triggering apoptosis.

Conclusions:

  • JunB displaces CoREST-RUNX, leading to apoptosis, revealing a convergent therapeutic vulnerability.
  • This JunB-mediated mechanism provides new avenues for optimizing combinatorial epigenetic therapy in cancer.

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