# Investigating how maternal metabolic dysfunction impacts mammalian gastrulation > **NIH NIH F31** · YALE UNIVERSITY · 2024 · $33,958 ## Abstract Despite the high prevalence of pregnancy loss during the early post-implantation period, a detailed understanding of cell and molecular workings at this stage of development remains elusive. During this period, specification of the principal lineages of the future body occurs at the gastrulation stage, an evolutionary conserved landmark event in life. While early embryonic cells are known to be sensitive to the changes in the metabolite availability in their immediate surroundings, extremely little is known about the role of the intrauterine metabolic environment during gastrulation and how it shapes embryo viability. The maternal metabolic environment can be disrupted via somatic mutations in metabolic enzymes, such as the gain-of-function mutation IDH2R140Q. This mutation leads to the conversion of the tricarboxylic acid cycle metabolite alpha-ketoglutarate (αKG) into the epigenetically active metabolite 2-hydroxyglutarate (2-HG), which subsequently accumulates in the bloodstream of affected patients and has downstream metabolic effects. In my preliminary work, I have modeled maternal metabolic dysfunction by inducing this mutation in adult females, and the resulting embryos demonstrate significant developmental delays at the time of gastrulation and failure to form distinct primary germ layers. My work also revealed increased histone methylation, as well as differential expression of genes involved in key developmental processes, such as cellular migration, as a response to 2-HG exposure in 2D cell culture. Collectively, these findings suggest that maternal metabolic dysfunction driven by mutant IDH is prohibitive to proper gastrulation. In light of these findings, I hypothesize that maternal 2-HG accumulation disrupts primary germ layer formation via both bioenergetic and epigenetic mechanisms. My first aim is to characterize the impact of IDH2R140Q-driven maternal metabolic dysfunction on primary germ layer formation. I will characterize the morphological effects of maternal 2-HG accumulation using high-resolution 3D confocal microscopy to investigate the spatiotemporal dynamics of germ layer cell specification and expansion. I further will characterize the changes in mitochondrial activity and cell death caused by maternal 2-HG accumulation using fluorescence-based assays. My second aim is to evaluate changes in the embryonic epigenetic landscape caused by maternal 2-HG accumulation. I will identify variable histone modifications in exposed embryos and the associated genomic loci using histone modification profiling followed by Cleavage Under Targets and Tagmentation (CUT&Tag) in the embryonic portion of gastrulas. Together, this project will pave the way toward a mechanistic and functional understanding of how maternal metabolic dysfunction modulates embryonic development as well as adverse pregnancy outcomes. Thus, in addition to providing me with valuable training that will further my career as a developmental biologist and reproductive ... ## Key facts - **NIH application ID:** 10995593 - **Project number:** 1F31HD116488-01 - **Recipient organization:** YALE UNIVERSITY - **Principal Investigator:** Jenna Bergmann - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $33,958 - **Award type:** 1 - **Project period:** 2024-09-01 → 2026-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10995593 ## Citation > US National Institutes of Health, RePORTER application 10995593, Investigating how maternal metabolic dysfunction impacts mammalian gastrulation (1F31HD116488-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10995593. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*