Evaluation of chromatin accessibility in cultured fetal hypothalamic neuroprogenitors following maternal protein
Valérie Amarger1, Morgane Frapin1, Pieter Vancamp1
1Nantes Université, INRAE, UMR 1280, PhAN, IMAD, F-44000, Nantes, France.
Insights
Maternal protein restriction alters fetal brain development by changing chromatin accessibility in hypothalamic cells. This may impact neurodevelopment and increase susceptibility to metabolic disorders later in life.
Area of Science:
- Neuroscience
- Developmental Biology
- Genomics
Background:
- Maternal protein restriction (PR) is linked to adverse fetal neurodevelopment and later-life neurometabolic disorders.
- While structural and transcriptomic changes are known, the regulatory mechanisms in the developing hypothalamus are unclear.
Purpose of the Study:
- To investigate if maternal PR alters chromatin accessibility in fetal hypothalamic neuroprogenitor cells.
- To identify the regulatory mechanisms disrupted by PR during critical neurodevelopmental periods.
Main Methods:
- ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) was performed on hypothalamic neuroprogenitors from gestational day 17 rat fetuses exposed to maternal PR.
- Motif enrichment analysis and RNA-seq were used to identify regulatory elements and gene expression changes.
- Integration with single-cell RNA-seq data was performed to associate gene expression with specific cell subpopulations.
Main Results:
- Identified 312 differentially accessible chromatin regions, with reduced accessibility near genes for MHC-I proteins, amino acid transporters, and neuronal differentiation factors.
- Observed altered transcription factor binding site accessibility (reduced FOS/JUN, enriched Krüppel-like factors).
- Identified 91 candidate genes with altered expression, enriched in cell proliferation, metabolism, and apoptosis pathways, though most accessibility changes did not significantly alter neighboring gene expression.
Conclusions:
- Maternal protein restriction alters chromatin accessibility in fetal rat hypothalamic progenitors.
- These epigenetic changes may represent a mechanism for fetal programming of neurodevelopmental and metabolic dysfunction.
- Provides a resource for studying chromatin regulation in the developing hypothalamus under nutritional stress.
Abstract:
Maternal protein restriction (PR) is a risk factor for altered fetal neurodevelopment and increased susceptibility to neurometabolic disorders later in life. Although structural and transcriptomic changes in the developing hypothalamus have been reported in PR-exposed offspring, the underlying regulatory mechanisms remain unclear. We hypothesized that maternal PR alters chromatin accessibility in hypothalamic neuroprogenitor cells, potentially disrupting gene regulation critical for cell fate specification. We performed ATAC-seq on hypothalamic neuroprogenitors isolated at gestational day 17 from rat fetuses that were exposed to an isocaloric PR diet. We identified 312 chromatin regions with different accessibility, including regions with reduced accessibility near genes encoding Major Histocompatibility Complex class I (MHC-I) proteins, amino acid transporters and proteins involved in neuronal differentiation, and synaptic signaling. Motif enrichment analysis revealed reduced accessibility at FOS/JUN and DBP binding sites in PR samples, alongside enrichment of Krüppel-like transcription factor motifs in more accessible regions. RNA-seq on neurospheres generated from these progenitors identified 91 candidate genes with altered expression patterns, enriched in pathways related to cell proliferation, protein-lipid metabolism, and apoptosis. Integration with previously generated single-cell RNA-seq data associated several of these genes with specific neuroprogenitor subpopulations. Except for two genes (RT1-A2 and Nav2), differences in chromatin accessibility were not associated with significant changes in neighboring gene expression. These findings provide an initial resource for exploring chromatin regulation in fetal rat hypothalamic progenitors. They suggest that maternal PR may influence developmental trajectories by altering chromatin accessibility and, consequently, be a mechanism underlying fetal programming of metabolic dysfunction.
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