SUV39H2 controls trophoblast stem cell fate.

Background: The placenta is formed by the coordinated expansion and differentiation of trophoblast stem (TS) cells along a multi-lineage pathway. Dynamic regulation of histone 3 lysine 9 (H3K9) methylation is pivotal to cell differentiation for many cell lineages, but little is known about its involvement in trophoblast cell development.

Methods: Expression of H3K9 methyltransferases was surveyed in rat TS cells maintained in the stem state and following differentiation. The role of suppressor of variegation 3-9 homolog 2 (SUV39H2) in the regulation of trophoblast cell lineage development was investigated using a loss-of-function approach in rat TS cells and ex vivo cultured rat blastocysts.

Results: Among the twelve-known H3K9 methyltransferases, only SUV39H2 exhibited robust differential expression in stem versus differentiated TS cells. SUV39H2 transcript and protein expression were high in the stem state and declined as TS cells differentiated. Disruption of SUV39H2 expression in TS cells led to an arrest in TS cell proliferation and activation of trophoblast cell differentiation. SUV39H2 regulated H3K9 methylation status at loci exhibiting differentiation-dependent gene expression. Analyses of SUV39H2 on ex vivo rat blastocyst development supported its role in regulating TS cell expansion and differentiation. We further identified SUV39H2 as a downstream target of caudal type homeobox 2, a master regulator of trophoblast lineage development.

Conclusions: Our findings indicate that SUV39H2 contributes to the maintenance of TS cells and restrains trophoblast cell differentiation.

General Significance: SUV39H2 serves as a contributor to the epigenetic regulation of hemochorial placental development.