Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid

Scientific Reports
Qing LiuMichael P Snyder

Abstract

13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal diffe...Continue Reading

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Citations

Jun 4, 2019·Journal of Developmental Biology·Eliyahu Perl, Joshua S Waxman
Jul 24, 2020·Archives of Toxicology·Karin LauschkeAnne Marie Vinggaard
Dec 2, 2020·Materials Science & Engineering. C, Materials for Biological Applications·Divya SridharanMahmood Khan

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Methods Mentioned

BETA
RNA-seq
flow cytometry
flow-cytometry
PCA
footprinting
Assay
PCR
electrophoresis
ATAC-seq

Software Mentioned

bg
Tophat 49
org
Pathview
PIQ package pertf
DAVID
Hs
common
MACS2
Picard

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