Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

Abstract

The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system. The villous syncytiotrophoblast carries most of these functions and provides the interface between the maternal and fetal circulatory systems. The syncytiotrophoblast is generated by the biochemical and morphological differentiation of underlying cytotrophoblast progenitor cells. The dysfunction of the villous trophoblast development is implicated in placenta-mediated pregnancy complications. Herein, we describe gene modules and clusters involved in the dynamic differentiation Int.Int. J. Mol. Sci. 2020, 21, 628 2 of 27 of villous cytotrophoblasts into the syncytiotrophoblast. During this process, the immune defense functions are first established, followed by structural and metabolic changes, and then by peptide hormone synthesis. We describe key transcription regulatory molecules that regulate gene modules involved in placental functions. Based on transcriptomic evidence, we infer how villous trophoblast differentiation and functions are dysregulated in preterm preeclampsia, a life-threatening placenta-mediated obstetrical syndrome for the mother and fetus. In the conclusion, we uncover the blueprint for villous trophoblast development and its impairment in preterm preeclampsia, which may aid in the future development of non-invasive biomarkers for placental functions and early identification of women at risk for preterm preeclampsia as well as other placenta-mediated pregnancy complications.

Dysregulation of Placental Functions and Immune Pathways in Complete Hydatidiform Moles

“…To evaluate absolute gene expression levels, mean expression values were calculated for both groups from RNA-Seq count data by normalizing for housekeeping genes. The highest expression in first trimester placentas was mostly detected for genes with placenta-specific or predominant placental expression [17,18,19]. Indeed, the 20 most highly-expressed genes (Table 1) included genes previously shown to have predominant placental ( n = 2) or placenta-specific ( n = 12) expression and unique placental functions in humans.…”

“…Since majority of these placenta-specific genes are most highly expressed in the trophoblast, we wished to learn whether their differential expression may reflect alterations in developmental or functional processes of the trophoblast. Therefore, we examined whether genes involved in villous trophoblast differentiation [19] (Figure 2A) are enriched among molar DE genes. However, we found only minimal enrichment (OR = 1.15, p = 0.006).…”

“…However, these studies were focusing on just a limited set of placenta-specific transcripts known to be differentially expressed during trophoblast differentiation, thus did not give a comprehensive insight into this important question. We recently discovered that abnormal villous trophoblast differentiation is at the root of the pathogenesis of early-onset preeclampsia, also reflected by profound placental dysregulation of placenta-specific genes [17,19]. Here we applied a similar non-targeted approach to investigate this issue.…”

“…Here we applied a similar non-targeted approach to investigate this issue. First, we intersected the list of DE genes in CHMs with the list of DE genes during villous trophoblast differentiation from our parallel study [19] and found only minimal enrichment for trophoblast differentiation genes in dysregulated genes in CHMs, much less than for placenta-specific genes. This suggests that trophoblast differentiation is moderately affected in CHMs, while the expression of placenta-specific genes is more extensively impacted.…”

“…We used Fisher’s exact test to test enrichment of the DE transcript set with genes previously demonstrated to have expression patterns of particular relevance: (1) genes with placenta-specific expression ( n = 164, Supplementary Table S2) [17]; (2) genes involved in villous trophoblast differentiation ( n = 1,937; GEO: GSE130339, the list was provided by authors of an unpublished work [19]); (3) genes imprinted in humans ( n = 209; imprinted gene databases, , Supplementary Table S3 and 4 genes related to immune processes ( n = 1,449; ; the final list is the manual curation and combination of Immport, Immunogenetic Related Information Source, and Immunome Database Gene Lists, Supplementary Table S4).…”