# Epigenetic and environmental impact on early embryonic development

> **NIH NIH DP2** · YALE UNIVERSITY · 2021 · $1,507,500

## Abstract

Project Summary/Abstract: During development, cellular diversity is achieved via the dynamic interpretation
of a fixed DNA template, a process that incorporates both straightforward genetic and obscure epigenetic
concepts. Cell identity is in part governed by transcription factor-directed programs, but these interact with
elaborate “codes” of post-translational modifications to chromatin that index regions of the genome for activity or
repression. To date, the general relationships between local chromatin remodeling and gene regulation have
been primarily modeled in cell lines and cannot yet account for the intricacy of the developing embryo. Moreover,
although many epigenetic regulators are essential for viable embryogenesis, it remains unclear how these
enzymes participate in specific developmental processes given the generic nature of their target substrates. A
detailed accounting of how epigenetic regulation operates during gestation is critical to understand complex
congenital or fetal disorders, which often have unclear penetrance, affect multiple cell types or tissue systems,
and can be highly influenced by the maternal environment. Here, I propose a transformative new strategy for
comprehensively phenotyping mutant embryos that incorporates detailed micromanipulation techniques, novel
molecular systems, and single cell analysis to recover high resolution morphological, molecular and temporal
information from many replicates simultaneously. My flexible approach permits rapid transition from hypothesis
to validation and eliminates many cumbersome aspects of traditional transgenics, as well as the frequent
limitation of examining only a limited number of lineages via a handful of pre-specified marker genes. I will apply
this pipeline to dissect the specific regulatory impact of maternal dietary folate and of the Polycomb group
repressors on early organogenesis, which represent “top-down” and “bottom-up” approaches to interpret
developmental robustness, the deliberate and reproducible generation of a sophisticated organism under
uncertain and fluctuating conditions. To do so, I will leverage my ability to recover data from mutant cohorts and
optimize new analytical strategies to quantify phenotypic variation and incomplete penetrance. These factors
are central concerns of reproductive medicine and have been extraordinarily challenging to reduce to clear
molecular mechanisms or pathways, subsequently limiting innovation of novel interventions and diagnostics. In
addition to addressing fundamental human health issues, these efforts will also substantially advance a suite of
new tools for exogenously titrating specific regulatory components as well as for recording the historical
relationship between single cells. If successful, this proposal will uncover previously opaque dimensions of
embryonic regulation, including shared and cell-type specific consequences of epigenetic or environmental
insults, as well as transform general methods for chara...

## Key facts

- **NIH application ID:** 10242497
- **Project number:** 1DP2HD108774-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Zachary Dylan Smith
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,507,500
- **Award type:** 1
- **Project period:** 2021-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242497

## Citation

> US National Institutes of Health, RePORTER application 10242497, Epigenetic and environmental impact on early embryonic development (1DP2HD108774-01). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10242497. Licensed CC0.

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