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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
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Hypoxia causes downregulation of mismatch repair system and genomic instability in stem cells

Francisco Javier Rodríguez-Jiménez1, Victoria Moreno-Manzano, Rut Lucas-Dominguez

  • 1Department Farmacología Molecular, Fundación Valenciana Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain. frodriguez@cipf.es

Stem Cells (Dayton, Ohio)
|May 31, 2008
PubMed

Insights

Hypoxia downregulates DNA mismatch repair (MMR) in stem cells, causing genomic instability. This may lead to cancer stem cell properties, highlighting risks in hypoxic environments.

Area of Science:

  • Genomics
  • Stem Cell Biology
  • Cancer Research

Background:

  • The DNA mismatch repair (MMR) system is crucial for genomic integrity, and its malfunction is linked to cancer.
  • Hypoxia-inducible factor-1alpha (HIF1alpha) and epigenetic factors can downregulate MMR genes in cancer cells.
  • Little is known about MMR regulation and stem cell genomic stability under hypoxia.

Purpose of the Study:

  • To investigate MMR gene expression and genomic stability in stem cells under hypoxic conditions.
  • To elucidate the roles of HIF1alpha and epigenetic modifications in MMR regulation during hypoxia in stem cells.

Main Methods:

  • Culturing murine and human stem cells under hypoxic conditions.
  • Utilizing short hairpin RNAi to assess HIF1alpha's role in MMR gene regulation.
  • Performing chromatin immunoprecipitation to analyze histone modifications and transcription factor binding.
  • Treating cells with a histone deacetylase inhibitor (trichostatin A).
  • Sequencing microsatellite markers to evaluate genomic stability.

Main Results:

  • MMR gene expression and DNA repair activity were reduced in stem cells cultured in hypoxia.
  • HIF1alpha positively regulated MLH1 and MSH6 under short-term hypoxia.
  • Prolonged hypoxia led to MMR gene downregulation via epigenetic changes (hypoacetylation/hypermethylation of histone H3) and reduced SP1 binding.
  • Histone deacetylase inhibition restored MMR gene expression.
  • Stem cells cultured in hypoxia exhibited genomic instability.

Conclusions:

  • Hypoxic environments can induce genomic instability in stem cells by downregulating the MMR system through epigenetic mechanisms.
  • This hypoxia-induced genomic instability in stem cells may contribute to the development of cancer stem cell properties.
  • These findings suggest that hypoxic niches are critical environments influencing stem cell genomic integrity and potentially cancer development.

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