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Epigenetic dysregulation from chromosomal transit in micronuclei

Albert S Agustinus1,2, Duaa Al-Rawi1,3, Bhargavi Dameracharla4

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature
|June 7, 2023
PubMed

Insights

Chromosomal instability (CIN) causes micronuclei formation, which disrupts histone modifications and chromatin accessibility. This epigenetic reprogramming contributes to cancer cell heterogeneity and progression.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Chromosomal instability (CIN) and epigenetic alterations are hallmarks of advanced and metastatic cancers.
  • The mechanistic link between CIN and epigenetic changes remains largely unknown.

Purpose of the Study:

  • To investigate the mechanistic link between chromosomal instability and epigenetic alterations in cancer.
  • To determine if micronuclei formation disrupts histone post-translational modifications (PTMs) and chromatin accessibility.

Main Methods:

  • Utilized orthogonal approaches to analyze histone PTMs and chromatin accessibility in cells with induced CIN and micronuclei.
  • Examined the impact of micronuclear envelope rupture on histone PTMs.
  • Assessed the heritability of epigenetic abnormalities after micronuclei reincorporation.

Main Results:

  • Micronuclei formation and rupture profoundly disrupt normal histone PTMs, a conserved phenomenon across species and cell types.
  • Micronuclei exhibit significant differences in chromatin accessibility with a positional bias.
  • CIN induces widespread epigenetic dysregulation, and chromosomes within micronuclei experience heritable accessibility defects.

Conclusions:

  • CIN promotes epigenetic reprogramming and cellular heterogeneity in cancer through disruption of histone PTMs and chromatin accessibility.
  • Micronuclei formation is a key driver of epigenetic dysregulation in cancer.
  • Understanding this link offers new avenues for cancer therapy targeting epigenetic vulnerabilities.

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