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In vivo Reprogramming of Adult Somatic Cells to Pluripotency by Overexpression of Yamanaka Factors
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In vivo Reprogramming of Adult Somatic Cells to Pluripotency by Overexpression of Yamanaka Factors

Published on: December 17, 2013

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Genomic instability during reprogramming by nuclear transfer is DNA replication dependent

Gloryn Chia1, Judith Agudo2, Nathan Treff3

  • 1Department of Pediatrics, Columbia University, New York 10032, USA.

Nature Cell Biology
|March 7, 2017
PubMed

Insights

Cellular reprogramming faces barriers beyond gene expression. Genetic instability, including DNA damage and chromosome errors, arises before full reprogramming and impacts developmental success.

Area of Science:

  • Cellular and Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Somatic cell reprogramming to pluripotency via nuclear transfer is crucial for regenerative medicine.
  • Developmental arrest frequently occurs, often linked to incomplete transcriptional reprogramming.
  • Reprogramming involves complex changes in cell cycle and nuclear structure, not just gene expression.

Purpose of the Study:

  • To investigate cellular reprogramming events in human and mouse nuclear transfer embryos before embryonic genome activation.
  • To determine the role of cell cycle progression and nuclear structure in reprogramming barriers.
  • To identify early events contributing to developmental failure independent of transcriptional changes.

Main Methods:

  • Analysis of nuclear transfer embryos (human and mouse) prior to embryonic genome activation.
  • Assessment of chromosome segregation, DNA damage, and cell cycle progression.
  • Investigation of BRCA1's role in DNA repair during reprogramming.
  • Study of mitotic nuclear remodeling effects on DNA replication and error rates.

Main Results:

  • Genetic instability, including chromosome segregation errors and DNA damage, occurs early in reprogramming, independent of transcriptional activity.
  • These errors arise after DNA replication and are repaired by BRCA1.
  • Delayed DNA replication and increased mitotic errors are observed in the absence of proper mitotic nuclear remodeling.
  • Cell cycle progression features act as a barrier to cell-type transition.

Conclusions:

  • Cell cycle progression, independent of gene expression, presents a significant barrier to somatic cell reprogramming.
  • Early genetic instability and DNA damage are critical factors influencing reprogramming success.
  • Understanding these cell cycle-dependent barriers is essential for improving reprogramming efficiency.

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