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

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-HIF-KDM3A-MMP12 regulatory circuit is conserved and facilitates placental adaptations to environmental challenges. placenta | hypoxia | trophoblast invasion | epigenetics | plasticity

KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

“…in line with the increasingly recognized role of KDM3A in environmental adaptation and mechanosensation (Chakraborty et al, 2016;Kaukonen et al, 2016;Pedanou et al, 2016). Immunopurification of endogenous KDM3A, two-hybrid screening, and far-Western blotting revealed that KDM3A interacts with actin in vivo and in vitro.…”

Histone methylation and vascular biology

“…The HIF signaling is a classic oxygen-sensitive pathway to regulate angiogenesis under hypoxic environments. Hypoxia activates Hifdependent expression of lysine demethylase 3A (Kdm3a) which demethylates H3K9 to accelerate Mmp12 expression to facilitate trophoblast invasion and uterine vascular remodeling [38].…”

Hypoxia and Placental Development

“…Exposure of TS cells to low oxygen can disrupt differentiation toward a trophoblast giant cell phenotype and instead promote development of the invasive trophoblast cell lineage (Cowden Dahl, Fryer, et al, 2005; Cowden Dahl, Robertson, et al, 2005; Gultice et al, ; Chakraborty et al, , ). These responses are dependent upon HIF signaling, which redirects the epigenetic landscape and gene expression of trophoblast cells (Chakraborty et al, , ). Hypoxia‐dependent HIF activation drives pivotal events, including the downregulation of E‐cadherin and upregulation of KDM3A, which promotes the expression of MMP12 and a pro‐invasive phenotype (Chakraborty et al, , ).…”

“…These responses are dependent upon HIF signaling, which redirects the epigenetic landscape and gene expression of trophoblast cells (Chakraborty et al, , ). Hypoxia‐dependent HIF activation drives pivotal events, including the downregulation of E‐cadherin and upregulation of KDM3A, which promotes the expression of MMP12 and a pro‐invasive phenotype (Chakraborty et al, , ).…”