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Fetal spina bifida associates with dysregulation in nutrient-sensitive placental gene networks: Findings from a
Marina White1, Jayden Arif-Pardy1, Tim Van Mieghem2
1Health Sciences, Carleton University, Ottawa, Ontario, Canada.
Insights
Spina bifida (SB) is linked to placental dysfunction and altered gene expression, particularly involving micronutrients beyond folic acid. Understanding these placental changes may reveal new targets to improve fetal outcomes in SB.
Area of Science:
- Genetics and Genomics
- Developmental Biology
- Obstetrics and Gynecology
Background:
- Spina bifida (SB) is a complex congenital anomaly requiring deeper understanding of its molecular underpinnings.
- Placental dysfunction is increasingly recognized as a contributing factor to adverse fetal outcomes.
Purpose of the Study:
- To investigate the association between fetal spina bifida and placental gene expression.
- To identify molecular drivers and nutrient-related pathways involved in SB-associated placental dysfunction.
Main Methods:
- Collected placental samples and clinical data from fetuses with isolated SB and controls.
- Performed placental transcriptome sequencing using Clariom D microarray.
- Applied a nutrient-focused gene expression analysis pipeline.
Main Results:
- Identified 391 differentially expressed genes (DEGs) in SB cases, with 11% linked to nutrient cofactors like B vitamins, iron, and zinc.
- Observed dysregulation in nutrient transport, angiogenesis, and immune processes in SB placentae.
- Found five nutrient-dependent transcription regulators, primarily influenced by B vitamins and zinc, targeting a significant portion of DEGs.
Conclusions:
- Placentae from fetuses with SB exhibit significant gene network dysregulation sensitive to multiple micronutrients.
- These findings highlight novel molecular mechanisms and potential therapeutic targets for improving fetal outcomes in SB.
- Placental gene expression alterations are more pronounced in cases with fetal growth restriction.
Abstract:
To improve outcomes in fetuses with spina bifida (SB), better understanding is needed of the molecular drivers of SB and its comorbidities. Pregnant people carrying a fetus with isolated SB (cases; n = 12) or a fetus with no congenital anomalies (controls; n = 21) were recruited at Mount Sinai Hospital, Toronto, Ontario, Canada. Clinical data and placental samples were collected. Placental transcriptome was sequenced (Clariom D microarray) and a nutrient-focused gene expression analysis pipeline was applied to determine whether fetal SB associates with placental dysfunction. Of the 391 differentially expressed genes (DEGs) in cases, 11% (n = 42) had at least one nutrient cofactor, including B vitamins (n = 7 genes), iron/heme (n = 6), and zinc (n = 11). Cases had dysregulation in genes not previously known to associate with SB, and in placental genes that have known links to SB but have not been previously identified in the placenta. Cases also had downregulated nutrient transport and upregulated branching angiogenesis and immune/inflammatory processes. Five nutrient-dependent transcription regulators, collectively predicted to target 46% of DEGs in cases, were identified and were most commonly dependent on B vitamins (n = 3) and zinc (n = 2). Placental gene expression changes were most acute in cases with poor growth. Placentae from fetuses with SB have dysregulation in several gene networks, including those that are sensitive to multiple micronutrients beyond the well-known folic acid. An improved understanding of placental phenotype in fetuses with SB may help identify novel mechanisms associated with comorbidities in fetuses with SB, and reveal new targets to improve fetal outcomes in this population.
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