# Early Environment, Developmental Epigenetics, and Adult Colonic Diseases

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $304,557

## Abstract

PROJECT SUMMARY
Gut microbial colonization in early postnatal life plays a crucial role in mammalian intestinal development. It
has long been postulated that DNA methylation, as an epigenetic mechanism to control gene expression, is
involved in intestinal host-microbial interactions. The high turnover of intestinal epithelial cells throughout life
makes intestinal stem cells (ISCs) critically important for gut function. Remarkably, however, how the
mechanisms underlying the effects of the gut microbiota on DNA methylation to regulate the emergence and
behavior of adult ISCs remain poorly understood. Improving our understanding of this process is fundamental
for human health because intestinal epithelium is one of the major tissue targets of inflammation and
tumorigenesis, and aberrant DNA methylation as well as alterations of the gut microbiota are increasingly
recognized to be critical for disease pathogenesis. The proposed research extends our previous work that
identified a subset of 3’ CpG islands (3’ CGIs) that are methylated in ISCs during the suckling period in mice.
We demonstrated that 3’ CGI methylation transmits an epigenetic memory associated with stable gene
activation in adult ISCs. In addition, we discovered that 3’ CGI methylation is uniquely vulnerable to gut
microbiota perturbations. Therefore, the goal of the proposed research is to further elucidate the mechanisms
of epigenetic regulation in developing ISCs. Our hypothesis is that postnatally established epigenetic memory
by 3’ CGI methylation provides a developmental pathway for regulating intestinal host-microbiome interactions
with lifelong functional consequences. We propose the following three specific aims: (i) Define the mechanism
by which 3’ CGI methylation regulates intestinal gene activation, (ii) Define the mechanism by which the gut
microbiota regulates 3’ CGI methylation, and (iii) Define the long-term function of microbiota-responsive 3’ CGI
methylation. We will capitalize on recent technological advancements enabling isolation of Lgr5+ ISCs; apply
state-of-the-art techniques to achieve the ultimate genome-wide, unbiased assessment of the microbiome
effects on the ISC epigenome; and use cutting-edge organoid and CRISPR epigenome editing tools to dissect
the microbiota-mediated epigenetic mechanisms that regulate ISC function. The successful completion of
these studies will yield important insights into the functional role of DNA methylation during intestinal
development, advancing our understanding of the molecular basis of gene-environment interactions in the
intestine. Furthermore, the mechanistic insight gained from these studies offers great promise for development
of interventions and treatments of intestinal diseases.

## Key facts

- **NIH application ID:** 10102263
- **Project number:** 5R01HD100914-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lanlan Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $304,557
- **Award type:** 5
- **Project period:** 2020-02-07 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102263

## Citation

> US National Institutes of Health, RePORTER application 10102263, Early Environment, Developmental Epigenetics, and Adult Colonic Diseases (5R01HD100914-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102263. Licensed CC0.

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