HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia

Damayanti Chakraborty, Wei Cui, Gracy X. Rosario, Regan L. Scott, Pramod Dhakal, Stephen J. Renaud, Makoto Tachibana, M. A. Karim Rumi, Clifford W. Mason, Adam Krieg, Michael J. Soares

Research output: Contribution to journalArticle

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Abstract

The hemochorial placenta develops from the coordinated multilineage differentiation of trophoblast stem (TS) cells. An invasive trophoblast cell lineage remodels uterine spiral arteries, facilitating nutrient flow, failure of which is associated with pathological conditions such as preeclampsia, intrauterine growth restriction, and preterm birth. Hypoxia plays an instructive role in influencing trophoblast cell differentiation and regulating placental organization. Key downstream hypoxia-activated events were delineated using rat TS cells and tested in vivo, using trophoblast-specific lentiviral gene delivery and genome editing. DNA microarray analyses performed on rat TS cells exposed to ambient or low oxygen and pregnant rats exposed to ambient or hypoxic conditions showed up-regulation of genes characteristic of an invasive/vascular remodeling/inflammatory phenotype. Among the shared up-regulated genes was matrix metallopeptidase 12 (MMP12). To explore the functional importance of MMP12 in trophoblast celldirected spiral artery remodeling, we generated an Mmp12 mutant rat model using transcription activator-like nucleases-mediated genome editing. Homozygous mutant placentation sites showed decreased hypoxia-dependent endovascular trophoblast invasion and impaired trophoblast-directed spiral artery remodeling. A link was established between hypoxia/HIF and MMP12; however, evidence did not support Mmp12 as a direct target of HIF action. Lysine demethylase 3A (KDM3A) was identified as mediator of hypoxia/HIF regulation of Mmp12. Knockdown of KDM3A in rat TS cells inhibited the expression of a subset of the hypoxia-hypoxia inducible factor (HIF)-dependent transcripts, including Mmp12, altered H3K9 methylation status, and decreased hypoxia-induced trophoblast cell invasion in vitro and in vivo. The hypoxia-HIFKDM3A-MMP12 regulatory circuit is conserved and facilitates placental adaptations to environmental challenges.

Original languageEnglish (US)
Pages (from-to)E7212-E7221
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number46
DOIs
StatePublished - Nov 15 2016

Fingerprint

Trophoblasts
Metalloproteases
Stem Cells
Hypoxia
Arteries
Placentation
Uterine Artery
Premature Birth
Cell Lineage
Microarray Analysis
Pre-Eclampsia
Oligonucleotide Array Sequence Analysis
Placenta
Methylation
Genes
Lysine
Cell Differentiation
Up-Regulation
Oxygen
Phenotype

Keywords

  • Epigenetics
  • Hypoxia
  • Placenta
  • Plasticity
  • Trophoblast invasion

ASJC Scopus subject areas

  • General

Cite this

HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. / Chakraborty, Damayanti; Cui, Wei; Rosario, Gracy X.; Scott, Regan L.; Dhakal, Pramod; Renaud, Stephen J.; Tachibana, Makoto; Karim Rumi, M. A.; Mason, Clifford W.; Krieg, Adam; Soares, Michael J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 46, 15.11.2016, p. E7212-E7221.

Research output: Contribution to journalArticle

Chakraborty, D, Cui, W, Rosario, GX, Scott, RL, Dhakal, P, Renaud, SJ, Tachibana, M, Karim Rumi, MA, Mason, CW, Krieg, A & Soares, MJ 2016, 'HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 46, pp. E7212-E7221. https://doi.org/10.1073/pnas.1612626113
Chakraborty, Damayanti ; Cui, Wei ; Rosario, Gracy X. ; Scott, Regan L. ; Dhakal, Pramod ; Renaud, Stephen J. ; Tachibana, Makoto ; Karim Rumi, M. A. ; Mason, Clifford W. ; Krieg, Adam ; Soares, Michael J. / HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 46. pp. E7212-E7221.
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AU - Tachibana, Makoto

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