# Global Analyses of the Placental Epigenome in Preeclampsia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $556,060

## Abstract

PROJECT SUMMARY/ABSTRACT
We theorize that the placental epigenome and its relationship to the transcriptome hold the key to
understanding pathways with important roles in the pathogenesis of severe preeclampsia (sPE). This
hypothesis is based on the association of sPE with certain placental pathologies. The cytotrophoblasts (CTBs)
that invade the uterine wall fail to differentiate properly; CTB invasion of the decidua is shallow and
endovascular invasion is constrained. Recently we found that CTBs of the smooth chorion also have very
significant sPE-associated morphological and molecular changes. Chorionic villi from affected pregnancies
have overt abnormalities as well such as syncytial knots. The investigators on this proposal—experts in
epigenomic analyses, biostatistics and bioinfomatics, data visualization and human placental biology—
completed detailed transcriptomic and epigenomic profiling, in the 2nd and 3rd trimesters of normal pregnancy,
of the areas that are disrupted in sPE—CTBs, the smooth chorion and chorionic villi. Whole genome bisulfite
sequencing (WGBS) confirmed hypomethylation of placental DNA and showed, for the first time, that large
blocks of hypomethylation were marked with gains in repressive H3K9me3. Patterns of DNA methylation were
unique to each sample type and trimester, suggesting dynamic regulation. As gestation advanced, many
regulatory regions of the CTB genome became methylated, suggesting epigenetic mechanisms regulating
functional alterations. Analyses of the corresponding RNA-seq data showed that CTB transcripts that were
highly expressed in 2nd trimester and downregulated at term included more genes that are overexpressed in
sPE than would be expected by chance. Exciting immunoblot (IB) data, corroborated by immunohistochemistry,
showed a novel and strong difference in histone modification levels between CTBs isolated from the placentas
of women diagnosed with sPE and control samples, matched for gestational age, that were isolated from the
placentas of women who had a preterm birth with no sign of infection (nPTL). We theorize that coalescing
epigenomic and transcriptomic data from CTBs, the smooth chorion and chorionic villi in sPE will reveal the
dysregulated pathways and new mechanistic insights. As to approach, we will use WGBS to profile DNA
methylation (Aim 1). We will employ IB and ChIP-seq to assess histone modifications—H3k27me3, H3k9me3,
H3K4me1, H3K4me3 and H3K27ac (Aim 2). Also, we will explore the translational potential of the findings by
asking whether the sPE-associated profile of dysregulated histone modifications can be detected in maternal
plasma. We will apply RNA-seq to investigate the consequences of epigenetic alterations at the mRNA level
and test the significance of the findings by using in vitro assays of TB functions (Aim 3). Results will be
publically available through the WashU Epigenome Browser. Thus, our results will reveal the role of the
epigenome in sPE-related changes in p...

## Key facts

- **NIH application ID:** 9920738
- **Project number:** 5R01HD092419-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Joseph F Costello
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,060
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920738

## Citation

> US National Institutes of Health, RePORTER application 9920738, Global Analyses of the Placental Epigenome in Preeclampsia (5R01HD092419-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9920738. Licensed CC0.

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