# Mechanisms of Transcriptional Regulation by MTG16 in the Intestine

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $51,036

## Abstract

PROJECT SUMMARY
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, affects 1.5 million people in
the United States. The incidence of colitis-associated cancer (CAC), or colorectal cancer in patients with IBD, is
nearly six-fold higher than that of the general population. Therefore, the morbidity and mortality of IBD is quite
high. Understanding the molecular mechanisms behind IBD and CAC pathogenesis may lead to improved
screening and therapeutics. Like other cancers driven by chronic inflammation, CAC is characterized by genetic
mutations and aberrant gene expression programs in intestinal cells. Leucine-rich repeat-containing G protein-
coupled receptor 5 (LGR5) is a membrane receptor that increases WNT signaling in intestinal stem cells,
conferring self-renewal and proliferation. Furthermore, LGR5+ stem cells are thought to be the cells-of-origin of
intestinal malignancy; thus, transcription of Lgr5 is tightly regulated. However, mechanisms of transcriptional
regulation of Lgr5 are largely unknown.
Myeloid translocation gene on chromosome 16 (MTG16) is a transcriptional co-repressor originally discovered
as a translocation fusion partner in therapy-related acute myeloid leukemia. Mtg16-/- mice exhibit aberrancies in
baseline intestinal phenotypes and increased susceptibility to chemical models of colitis and CAC. Preliminary
data using a luciferase reporter assay and chromatin immunoprecipitation (ChIP) indicate that MTG16 represses
Lgr5 expression through occupancy of intron 1 of Lgr5. Using a yeast two-hybrid screen and protein complex
immunoprecipitation (Co-IP), we identified the elongation factors MLL1, AFF4, and DOT1L as potential MTG16
interacting partners. Mutation or deletion of certain Nervy homology regions (NHRs) in MTG16 abolished
interaction in yeast two-hybrid growth assays and increased the severity of dextran sodium sulfate-induced colitis
in vivo. Taken together, we hypothesize that specific NHRs in MTG16 bind to transcription and elongation factors
to regulate Lgr5 expression, impacting homeostasis, injury, and tumorigenesis in the intestinal epithelium.
This hypothesis will be tested via two focused, mechanistic, and hypothesis-driven Aims. In Specific Aim 1, the
components of the endogenous MTG16 repression complex of Lgr5 in the intestine will be elucidated using Co-
IP and sequential ChIP in in young adult mouse colon (YAMC) cells. Lentiviral overexpression of mutant MTG16
in a previously CRISPR-generated MTG16-deficient YAMC line will be used to determine NHR dependency of
complex formation and Lgr5 repression in intestinal cells. In Specific Aim 2, novel MTG16 NHR mutant mice will
be used to test for NHR dependency on intestinal epithelial homeostasis, injury, and tumorigenesis. Importantly,
clarifying the role of MTG16 in intestinal epithelial biology will further our understanding of stem cell biology and
may elucidate novel mechanisms for targeting pro-proliferative and tumorigenic p...

## Key facts

- **NIH application ID:** 10229518
- **Project number:** 5F30DK120149-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Rachel Elizabeth Brown
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229518

## Citation

> US National Institutes of Health, RePORTER application 10229518, Mechanisms of Transcriptional Regulation by MTG16 in the Intestine (5F30DK120149-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229518. Licensed CC0.

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