Biology subjects

Sadovsky, Y.

Publications and source records attributed to Sadovsky, Y..

6 recordsLinked to original sources

bioRxiv2026

The Epigenetic Factor PHF13 Governs Trophoblast Stemness and Differentiation

Differentiation of trophoblast stem (TS) cells or progenitor cytotrophoblasts (CTBs) into multinucleated syncytiotrophoblasts (STBs) is essential for placental development. Disruption of this process contributes to major obstetrical syndromes, including fetal growth restriction and preeclampsia, and Trisomy 21. However, the chromatin mechanisms governing trophoblast stemness and differentiation remain inadequately defined. Here we identify the chromatin-associated factor PHF13, uncovered through a high-throughput microRNA target screen, as a key regulator of trophoblast cell fate. PHF13 knockout TS cells exhibited defects that ultimately resulted in loss of cell viability, whereas PHF13 knockdown promoted expression of fusion-associated genes, including ERVFRD-1 and human chorionic gonadotropin (hCG). Consistently, PHF13 depletion in BeWo trophoblast cells increased hCG expression and secretion while reducing expression of canonical stemness-associated transcription factors ELF5 and TEAD4. Integrated genomic analyses further revealed that PHF13 target genes comprise a gene regulatory network that maintains trophoblast stemness and restrains differentiation. Notably, the pluripotency-associated transcription factor THAP11 partially co-occupies genomic sites with PHF13. Together, these findings establish PHF13 as a previously unrecognized chromatin regulator of trophoblast stemness and differentiation, providing mechanistic insight into pathways critical for placental development and function. HighlightsO_LIPHF13 preserves trophoblast stem cell identity C_LIO_LIPHF13 restrains syncytiotrophoblast differentiation C_LIO_LIPHF13 controls trophoblast chromatin programs with THAP11 C_LI

molecular biology↗

bioRxiv2025

The Chromosome 19 miRNA Cluster Guards Trophoblasts Against Overacting Innate Immunity

To maintain pregnancy health, the human placenta delicately balances protection of the developing fetus from invading pathogens with suppression of excessive inflammation that could lead to fetal and neonatal autoimmune disorders. Previous research, including our own, has shown that small RNA products of the Chromosome 19 MicroRNA Cluster (C19MC) promote viral resistance in non-trophoblastic cells. However, the role of C19MC products in placental trophoblasts remained unclear. Here, we analyzed chromatin accessibility in the C19MC enhancer and identified a previously unknown regulatory domain. Deletion of this domain silenced the expression of C19MC microRNA and Alu elements in trophoblasts. This silencing unexpectedly led to marked activation of cellular innate immune response and strikingly increased Toll-like receptor 3 (TLR3)-mediated sensitivity to poly(I:C), a viral RNA mimic. Our data suggest that C19MC non-coding RNAs interfere with endosomal TLR3 activation in trophoblasts, highlighting a previously unrecognized mechanism for hindrance of excessive innate immune activation.

developmental biology↗

bioRxiv2024

Placental Network Differences Among Obstetric Syndromes Identified With An Integrated Multiomics Approach

The placenta is essential for a healthy pregnancy, and placental pathology can endanger both maternal and fetal health. Placental function is affected by dynamic, complex, and interconnected molecular, cellular, and environmental events; therefore, we need a systems biology approach to study disease in normal physiological placenta function. We use placental multiomics (short and bulk transcriptomics, untargeted metabolomics, and targeted proteomics) paired with clinical data and placental histopathology reports from 321 placentas across multiple obstetric conditions: fetal growth restriction (FGR), FGR with pregnancy-related hypertension (FGR+HDP), preeclampsia (PE), and spontaneous preterm delivery (PTD). We first performed cellular deconvolution to estimate cell type numbers from bulk transcriptomes: FGR+HDP placentas were the most different from control placentas driven by a higher estimated number of extravillous trophoblast (p<0.0001). Next, we evaluated the impact of fetal sex and gestational age on analyte levels, adjusting for these confounders. We then generated obstetric condition-specific correlation networks and identified communities of related analytes associated with physiology and disease. We demonstrated how network connectivity and its disruption in disease can be used to identify signatures unique to a clinical outcome. We examined a community defined in control placentas for which the most connected node was miR-365a-3p in contrast to the corresponding community in FGR+HDP placentas for which the most connected node was hypoxia-induced miR-210-3p. From this community, we identified a signature containing mRNA transcripts implicated in placental dysfunction (e.g. FLT1, FSTL3, HTRA4, LEP, and PHYHIP). This signature distinguishes between FGR+HDP placentas and placentas of differing clinical outcomes in high-dimensional space. These findings illustrate the power of systems biology-driven interomics network analysis in a single tissue type, laying the groundwork for future multi-tissue studies.

systems biology↗

bioRxiv2023

Lipid nanoparticle structure and delivery route during pregnancy dictates mRNA potency, immunogenicity, and health in the mother and offspring

Treating pregnancy-related disorders is exceptionally challenging because many small molecule drugs on the market may cause maternal and fetal toxicity. This potential danger has hindered the development and clinical evaluation of new drugs for several decades. Lipid nanoparticle (LNP)-based RNA therapies with high delivery efficacy, favorable immune response, and minimal transplacental transport can quell maternal-fetal toxicity concerns and propel the development of pregnancy-safe drugs. To this extent, we report potent LNP structures that robustly deliver mRNA to maternal organs and placenta. Using structure-function analysis, we show that LNP efficacy is influenced by the polyamine headgroup, and toxicity is governed by the acrylate tail. Our lead nanoparticle shows robust protein expression via multiple clinically relevant administration routes in pregnant mice. In the placenta, it transfects trophoblasts, endothelial cells, and immune cells. Further, by varying ionizable lipid structure, we demonstrate that LNP immunogenicity affects organ expression and pup health during pregnancy. Immunogenic LNPs show lower efficacy in lymphoid organs in an IL-1{beta} dependent manner in pregnant mice. Further, pro-inflammatory immune responses provoke the infiltration of adaptive immune cells in the placenta and restrict pup growth after birth. Together, our results provide a mechanistic basis for designing safe and potent LNPs that can be administered during pregnancy.

bioengineering↗

bioRxiv2022

A Genome Scale Transcriptional Regulatory Model of the Human Placenta

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

systems biology↗

bioRxiv2017

Human placental syncytiotrophoblasts restrict Toxoplasma gondii vertical transmission at two distinct stages and induce CCL22 in response to infection

Toxoplasma gondii is a major source of congenital disease worldwide, but the cellular and molecular factors associated with its vertical transmission are largely unknown. In humans, the placenta forms the key interface between the maternal and fetal compartments and forms the primary barrier that restricts the hematogenous spread of microorganisms. Here, we utilized primary human trophoblast (PHT) cells isolated from full-term placentas and human mid-gestation chorionic villous explants to determine the mechanisms by which human trophoblasts restrict and respond to T. gondii infection. We show that placental syncytiotrophoblasts, multinucleated cells that are in direct contact with maternal blood, restrict T. gondii infection at distinct stages of the parasite lytic cycle--at the time of attachment and also during intracellular replication. Utilizing comparative RNAseq transcriptional profiling, we also show that human placental trophoblasts at both mid- and late-stages of gestation induce the chemokine CCL22 in response to T. gondii infection, which relies on the secretion of parasite effector(s). Collectively, our findings provide new insights into the mechanisms by which the human placenta restricts the vertical transmission of T. gondii at early and late stages of human pregnancy, and demonstrate the existence of at least two interferon-independent pathways that restrict T. gondii access to the fetal compartment.\n\nSignificance statementToxoplasma gondii is a major source of congenital disease worldwide and must breach the placental barrier to be transmitted from maternal blood to the developing fetus. The events associated with the vertical transmission of T. gondii are largely unknown. Here, we show that primary human syncytiotrophoblasts, the fetal-derived cells that comprise the primary placental barrier, restrict T. gondii infection at two distinct stages of the parasite life cycle and respond to infection through the induction of the chemokine CCL22. Collectively, our findings provide important insights into the mechanisms by which human syncytiotrophoblasts restrict T. gondii infection at early and late stages of human pregnancy and identify the placental-enriched signaling pathways induced in response to infection.

microbiology↗