Combinatorial knockout of RARα, RARβ, and RARγ completely abrogates transcriptional responses to retinoic acid in murine embryonic stem cells

The Journal of Biological Chemistry
Kristian B Laursen, Lorraine J Gudas

Abstract

All-trans-retinoic acid (RA), a potent inducer of cellular differentiation, functions as a ligand for retinoic acid receptors (RARα, β, and γ). RARs are activated by ligand binding, which induces transcription of direct genomic targets. However, whether embryonic stem cells respond to RA through routes that do not involve RARs is unknown. Here, we used CRISPR technology to introduce biallelic frameshift mutations in RARα, RARβ, and RARγ, thereby abrogating all RAR functions in murine embryonic stem cells. We then evaluated RA-responsiveness of the RAR-null cells using RNA-Seq transcriptome analysis. We found that the RAR-null cells display no changes in transcripts in response to RA, demonstrating that the RARs are essential for the regulation of all transcripts in murine embryonic stem cells in response to RA. Our key finding, that in embryonic stem cells the transcriptional effects of RA all depend on RARs, addresses a long-standing topic of discussion in the field of retinoic acid signaling.

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Citations

Feb 10, 2019·The Journal of Biological Chemistry·Ryan N SerioLorraine J Gudas
Jun 9, 2020·BioMed Research International·Min WangXin-Xin Han
May 9, 2019·Genesis : the Journal of Genetics and Development·Suya Wang, Alexander R Moise
Jan 25, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Ioan Ovidiu SirbuAlexander Radu Moise
Feb 1, 2019·Pharmacology & Therapeutics·William S Blaner
Mar 2, 2021·American Journal of Physiology. Renal Physiology·Anqun ChenJohn Cijiang He
May 1, 2021·International journal for vitamin and nutrition research. Internationale Zeitschrift für Vitamin- und Ernährungsforschung. Journal international de vitaminologie et de nutrition·Harald CarlsenRune Blomhoff
Sep 14, 2021·Annual Review of Pharmacology and Toxicology·Lorraine J Gudas

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