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WDR5, BRCA1, and BARD1 Co-regulate the DNA Damage Response and Modulate the Mesenchymal-to-Epithelial Transition

Georgina Peñalosa-Ruiz1, Vicky Bousgouni2, Jan P Gerlach1

  • 1Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6500 HB, the Netherlands.

Stem Cell Reports
|March 19, 2019
PubMed

Insights

Researchers screened 300 chromatin factors to understand cellular requirements for reprogramming differentiated cells into induced pluripotent stem cells. They identified key factors like BRCA1, BARD1, and WDR5 influencing reprogramming efficiency and cell transition.

Area of Science:

  • Cellular reprogramming
  • Epigenetics
  • Stem cell biology

Background:

  • Differentiated cells possess epigenetic stability but can be reprogrammed to pluripotency using OSKM transcription factors.
  • Understanding the cellular requirements and their impact on induced pluripotent stem cells (iPSCs) remains a significant challenge.

Purpose of the Study:

  • To identify chromatin-associated factors crucial for cellular reprogramming.
  • To characterize the cellular phenotypes and transcriptional changes during early reprogramming.
  • To elucidate the functional interactions of identified factors in reprogramming.

Main Methods:

  • High-content screening using small interfering RNAs (siRNAs) targeting 300 chromatin-associated factors.
  • Quantitative feature extraction from colony morphology.
  • RNA sequencing to analyze transcriptional changes.
  • Double knockdown epistasis experiments to determine functional interactions.

Main Results:

  • Identified five distinct morphological phenotypes during early reprogramming, including one indicating an early reprogramming block.
  • Discovered that BRCA1, BARD1, and WDR5 functionally interact and are essential for the DNA damage response during reprogramming.
  • Observed that knockdown of Brca1, Bard1, and Wdr5 impacts the mesenchymal-to-epithelial transition.

Conclusions:

  • Colony morphology serves as a valuable high-dimensional readout for assessing reprogramming quality.
  • Provides a comprehensive resource of chromatin-associated factors involved in early cellular reprogramming.
  • Highlights the critical roles of BRCA1, BARD1, and WDR5 in reprogramming efficiency and cellular transitions.
Keywords:
BARD1BRCA1DNA damage repairWDR5chromatin factorsfunctional interactionsiPSCsmesenchymal-to-epithelial transitionreprogramming

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