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Heritable transcriptional defects from aberrations of nuclear architecture

Stamatis Papathanasiou1,2,3, Nikos A Mynhier4,5, Shiwei Liu5,6

  • 1Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. s.papathanasiou@imb-mainz.de.

Nature
|June 7, 2023
PubMed

Insights

Cancer cells exhibit transcriptional heterogeneity, driven by epigenetic changes. This study reveals that micronuclei and chromosome bridges cause heritable gene silencing, contributing to tumour evolution and drug resistance.

Area of Science:

  • Genetics
  • Epigenetics
  • Cancer Biology

Background:

  • Transcriptional heterogeneity in cancer arises from epigenetic plasticity, impacting tumor evolution, metastasis, and drug resistance.
  • The precise mechanisms driving this epigenetic variation remain largely unknown.

Purpose of the Study:

  • To identify the sources of heritable transcriptional suppression in cancer cells.
  • To elucidate the role of nuclear aberrations, specifically micronuclei and chromosome bridges, in epigenetic variation and gene expression.

Main Methods:

  • Utilized long-term live-cell imaging to observe nuclear dynamics.
  • Employed same-cell single-cell RNA sequencing (Look-Seq2) to analyze gene expression changes within individual cells.
  • Investigated epigenetic marks and DNA damage associated with nuclear aberrations.

Main Results:

  • Identified micronuclei as sources of heritable transcriptional suppression, with reduced gene expression in chromosomes within micronuclei.
  • Demonstrated that gene expression changes can be inherited even after micronuclear chromosomes re-enter the main nucleus.
  • Observed acquisition of aberrant epigenetic marks and long-lived DNA damage on micronuclear chromosomes, leading to persistent transcriptional repression and reduced chromatin accessibility.

Conclusions:

  • Micronuclei and chromosome bridges are significant sources of heritable transcriptional suppression in cancer.
  • Epigenetic alterations in transcription are intrinsically linked to chromosomal instability and nuclear architecture defects.
  • These findings offer insights into tumour evolution, metastasis, and drug resistance mechanisms driven by epigenetic plasticity.

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