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Let-7c-5p Drives Collagen Gene Repression Linking Phenobarbital Teratogenicity to Cleft Palate

Annalisa Palmieri1, Luca Scapoli1, Agnese Pellati2

  • 1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

The American Journal of Pathology
|May 7, 2026
PubMed

Insights

Phenobarbital (PB) exposure during pregnancy can cause cleft palate (CP) by altering microRNA (miRNA) expression. This study shows PB-induced let-7c-5p upregulation represses collagen genes, linking PB teratogenicity to CP pathogenesis.

Area of Science:

  • Developmental biology
  • Epigenetics
  • Pharmacology

Background:

  • Anticonvulsant use during pregnancy, like phenobarbital (PB), poses risks for congenital malformations such as cleft palate (CP).
  • MicroRNAs (miRNAs) are crucial regulators of palatogenesis and may be affected by teratogenic drugs.
  • Previous studies identified specific miRNA dysregulation in CP patients.

Purpose of the Study:

  • To investigate if miRNA dysregulation in CP patients is due to epigenetic changes induced by PB.
  • To explore the role of specific miRNAs, like let-7c-5p, in PB-induced teratogenicity and CP development.

Main Methods:

  • Treated human embryonic palatal mesenchymal (HEPM) cells with PB and analyzed miRNA expression.
  • Compared miRNA profiles in PB-treated cells with those from CP patient tissues.
  • Utilized bioinformatic analysis to predict targeted pathways, focusing on collagen genes.
  • Validated collagen gene expression using quantitative RT-PCR and performed functional inhibition of let-7c-5p.

Main Results:

  • PB treatment altered miRNA expression in HEPM cells, notably downregulating miR-29b-3p and upregulating let-7c-5p, mirroring CP patient data.
  • Bioinformatic analysis and validation confirmed collagen fibril organization as a targeted pathway.
  • Downregulation of key collagen genes (COL1A2, COL3A1) was observed in both PB-treated cells and CP tissues.
  • Inhibition of let-7c-5p reversed PB-induced collagen gene repression.

Conclusions:

  • A shared epigenetic regulatory mechanism involving let-7c-5p and collagen genes links PB teratogenicity to CP.
  • let-7c-5p acts as a mediator of collagen gene repression in response to PB exposure.
  • These findings offer new insights into extracellular matrix remodeling during palatogenesis and PB-induced CP.

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