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Inhibition of histone H3-H4 chaperone pathways rescues C. elegans sterility by H2B loss

Ruixue Zhao1, Zhiwen Zhu1, Ruxu Geng1

  • 1Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, McGovern Institute for Brain Research, School of Life Sciences and MOE Key Laboratory for Protein Science, Tsinghua University, Beijing, China.

Plos Genetics
|June 9, 2022
PubMed

Insights

Loss-of-function oncohistone mutations cause cancer. Researchers found that decreasing histone H3-H4 levels in C. elegans rescues defective H2B, suggesting H3-H4 chaperone inhibition as a cancer therapy.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Oncohistone mutations are key drivers of cancer.
  • The mechanisms by which organisms manage loss-of-function oncohistones are not fully understood.
  • Histone H2B mutations can lead to tumorigenesis.

Purpose of the Study:

  • To investigate how loss-of-function oncohistones are regulated in vivo.
  • To identify potential therapeutic strategies for oncohistone-driven cancers.

Main Methods:

  • Generated a histone H2B triple knockout (3KO) Caenorhabditis elegans strain.
  • Conducted genetic suppressor screens to identify mutations that restore fertility in H2B 3KO mutants.
  • Utilized RNA interference (RNAi) to target H3-H4 chaperones and histones.

Main Results:

  • The H2B 3KO strain exhibited decreased embryonic H2B, disrupted cell division, and sterility.
  • Mutations in the histone H3-H4 chaperone UNC-85 restored fertility in H2B 3KO mutants by reducing chromatin H3-H4 levels.
  • RNAi of other H3-H4 chaperones or H3/H4 histones also rescued H2B 3KO sterility.
  • Inhibiting H3-H4 chaperones restored cell division in C. elegans with the oncohistone H2BE74K mutation.

Conclusions:

  • Reducing chromatin H3-H4 levels can rescue dysfunctional H2B in vivo.
  • Inhibiting H3-H4 chaperones represents a potential therapeutic strategy for cancers caused by loss-of-function H2B oncohistones.

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