Biology subjects

Dreyfuss, J.

Publications and source records attributed to Dreyfuss, J..

4 recordsLinked to original sources

bioRxiv2025

MICRORNAS REGULATED BY PREGNANCY TARGET THE HIV INTERACTOME

Innate immunity predictors of HIV risk are influenced by reproductive hormone levels, pregnancy, and lactation status. However, the molecular mechanisms underlying these associations remain unclear. MicroRNAs (miRNAs), as post-transcriptional regulators, play key roles in immune regulation and host-virus interactions. We hypothesized that physiological adaptations to pregnancy include the modulation of systemic miRNA expression, which in turn regulates host genes involved in HIV interaction, potentially influencing susceptibility during pregnancy. To test this, we leveraged a large longitudinal cohort from Uganda and Zimbabwe and analyzed 174 serum samples from 88 participants in pre-pregnancy (PP), pregnancy (P), and breastfeeding (BF) states using the HTG EdgeSeq platform. Differentially expressed (DE) miRNAs in pregnancy were identified with false discovery rate (FDR) < 0.1 (29 upregulated and 131 downregulated) by intersecting pairwise comparisons (P vs. PP and P vs. BF). Validated gene targets (2,733) were identified via miRWalk and modular enrichment analysis performed using Cytoscape/ClueGO. Enriched pathways (FDR<0.05) included Adaptive Immune Response, Hippo Signaling, Cellular Senescence, HSV-1 Infection, and two cancer-related pathways. Genes from pregnancy-enriched pathways overlapped with the known HIV-host interactome at the range of 37 to 88%. From this overlap, the Maximal Clique Centrally (MCC) score (cytoHubba) identified 47 unique hub genes acting as essential regulatory nodes of protein-protein interaction (PPI) network. These hub genes were further examined by their expression patterns predicted by DE miRNAs, and explored for their interactions with the HIV interactome, revealing connectivity with 18 HIV proteins - highest with Tat and gp120 - and impact on the HIV replication process. HLA-A was the most connected host gene, followed by BCL2L1, EIF2AK2, PTEN, and CYCS. These findings support the hypothesis that pregnancy-driven systemic miRNAs may shape HIV susceptibility by regulating hub genes with central role in viral evasion of host immunity. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/665982v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1cd2007org.highwire.dtl.DTLVardef@1f1b9d3org.highwire.dtl.DTLVardef@dee856org.highwire.dtl.DTLVardef@6796c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

MICRORNAS AS REGULATORS OF DRUG METABOLISM AND TRANSPORT IN PREGNANT AND LACTATING WOMEN

BackgroundPhysiological changes during pregnancy result in altered maternal drug metabolism that impacts efficacy and safety of therapeutics in pregnant women. Pregnancy induced hormonal, immunologic, or metabolic changes may also influence and alter drug disposition. Despite research efforts focused on pharmacokinetics of medications used in pregnant women in the past decade, knowledge gaps exist in understanding how pregnancy influences drug disposition and placental drug transporters. Moreover, there is a scarcity of research in understanding the safety and effectiveness of therapeutics in lactating women. This study aimed to determine the effect of pregnancy on levels of miRNAs regulating drug metabolizing enzymes and transporters (DMET). MethodsWe utilized longitudinal serum specimens collected in 3-month intervals from 88 women who became pregnant during follow-up in a large prospective study of hormonal contraception and HIV acquisition in Uganda and Zimbabwe. We used the HTG EdgeSeq platform coupled with Illumina sequencing to obtain the global miRNA transcriptome in paired specimens collected before, during and after pregnancy. To identify differentially expressed (DE) miRNAs that distinguish pregnancy from pre-conception or breastfeeding we used mixed effect model accounting for multiple samples from the pregnancy event and controlling for fixed effects of batch, country, Nugent score category and sexually transmitted infections. To identify hormonally regulated miRNAs independently associated with Box-Cox-transformed levels of progesterone (P4), {beta}-estradiol (E2), and sex-hormone binding protein (SHBG) we controlled in addition for age, pregnancy and breastfeeding P-values were corrected using the Benjamini-Hochberg false discovery rate (FDR). DMET-targeting miRNAs were identified using miRTarBase focusing on interactions verified by 3-UTR luciferase reporter assay and overlapped with DE miRNAs with FDR < 0.05. ResultsOf 140 DMET-targeting miRNAs among the 2079 miRNAs in the global peripheral blood transcriptome, 41 unique DMET-targeting miRNAs were found to be DE during pregnancy - 38 differentiating pregnancy from preconception and 9 differentiating pregnancy from breastfeeding. The 56 DMETs confirmed as targets of the DE miRNAs included 8 members of the ABC (ATP-binding cassette) transporter family, all abundantly expressed in the placenta, and 4 members of the cytochrome P450 Phase 1 enzyme family with major role in xenobiotics detoxification. The study also revealed a strong (FDR<0.05), predominantly positive association between specific DMET-targeting miRNAs and sex hormone-binding globulin (SHBG) levels, suggesting a miRNA-mediated downregulation of DMETs as SHBG levels rise during pregnancy. ConclusionThis research provides crucial insights into the molecular mechanisms underlying altered drug disposition in pregnant and lactating women, paving the way for improved therapeutic management and personalized medicine in these populations.

molecular biology↗

bioRxiv2025

Abnormal Vaginal Microbiota Associated with miRNA Targeting the HIV-Host Interactome

Understanding the molecular mechanisms underlying the ability of vaginal dysbiosis to alter the mucosal barrier to HIV acquisition is an essential step toward prevention. We hypothesized that micro(mi)-RNAs dysregulated by vaginal pathobiont bacteria epigenetically control host pathways exploited by the virus. The impact of these endogenous non-coding short RNAs on the anti-viral mucosal barrier function in the female reproductive tract is largely unknown. This study utilized cervicovaginal specimens collected during the luteal and follicular phase of the menstrual cycle along with data on age, race, ethnicity, education, and body mass index from 141 healthy reproductive-age women confirmed negative for sexually transmitted infections. Vaginal microbiota was classified by Nugent scoring. Shot-gun vaginal microbiome sequencing and metagenome taxonomic classification was performed on a subset of 21 women. Levels of miRNAs in exosomes isolated from cervicovaginal secretions were quantified using the EdgeSeq-NextGen global transcriptome platform. Differential expression (DE) was determined using R. Epigenetic target prediction was performed using MirTarBase. MiRNA profiles varied by both Nugent score categories (0-3 scores = normal, 4-6 = intermediate, and 7-10 = bacterial vaginosis, BV) and by metagenome classification. Higher microbiome diversity was associated with higher number of significantly dysregulated miRNAs (588 in BV compared to Nugent 0-3 versus 42 in Nugent 4-6 compared to Nugent 0-3, false discovery rate FDR<0.01) affecting over 400 experimentally validated genes targeted for post-transcriptional regulation. The miRNAs dysregulated by G. vaginalis-dominated compared to L. crispatus-dominated metagenomes included 24 DE miRNAs (92% overlap with BV by Nugent score) and 112 validated target genes. BV-dysregulated miRNA mediated the immunosuppressive effects of BV on cytokine levels previously associated with HIV acquisition risk. The gene ontology predictions based on BV-dysregulated miRNAs identified enrichment for 445 downregulated and 50 upregulated genes previously validated as part of the HIV-host interactome. miRNAs mediation revealed a mechanism of suppressed immunity by BV predictive of HIV risk. In conclusion, miRNAs dysregulated by vaginal dysbiosis may facilitate immune imbalance and cellular pathways associated with HIV risk.

molecular biology↗

bioRxiv2019

Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.

systems biology↗