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Employing Multi-Omics Analyses to Understand Changes during Kidney Development in Perinatal Interleukin-6 Animal
Ganesh Panzade1, Tarak Srivastava2,3, Daniel P Heruth4
1Christopher S. Bond Life Sciences Center, University of Missouri-Columbia, Columbia, MO 65211, USA.
Insights
Maternal inflammation during pregnancy, specifically elevated interleukin-6 (IL-6), alters fetal kidney gene expression. This epigenetic and miRNA dysregulation may program offspring for chronic kidney disease (CKD).
Area of Science:
- Developmental Biology
- Genomics
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is a major global health concern.
- Maternal obesity and inflammation, marked by elevated interleukin-6 (IL-6), are linked to adverse intrauterine development.
- Previous studies showed maternal IL-6 impacts fetal development in mice.
Purpose of the Study:
- To investigate how IL-6-induced maternal inflammation affects fetal kidney gene expression and epigenetic modifications.
- To identify key genes and regulatory pathways disrupted by gestational inflammation.
Main Methods:
- Pregnant mice were exposed to IL-6 or saline during mid-gestation.
- Newborn mouse kidneys were analyzed using multi-omics: mRNA-seq, miRNA-seq, and whole-genome bisulfite sequencing (WGBS).
- Bioinformatics and data integration identified key genes regulated by epigenetics and miRNAs.
Main Results:
- A multi-omics approach identified 19 key genes regulated by DNA methylation and microRNAs (miRNAs).
- Disruptions were observed in pathways including O-glycan biosynthesis, cell cycle, apoptosis, and FoxO signaling.
- Specific genes like Atp7b and Man2a1 showed altered regulation via DNA methylation and miRNA targeting.
Conclusions:
- Gestational inflammation mediated by IL-6 can induce epigenetic and miRNA changes in the developing fetal kidney.
- These molecular alterations in key genes may contribute to fetal programming for later-life diseases, including CKD.
Abstract:
Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation.
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