# Competitive interplay of neuronal transcription factors via DNA methylation

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $193,631

## Abstract

Abstract
In the brain, the transcription factors MeCP2 and CREB play crucial roles in activity-dependent gene
regulation for long-term memory formation and learning. Dysfunction of these proteins is associated with
brain disorders such as Rett syndrome and drug addiction. MeCP2 was originally identified as a
transcriptional repressor that specifically recognizes methylated CpG dinucleotides in DNA. More recently,
despite the lack of any known transcriptional activation domain, it was found that neuronal MeCP2 activates
more than 2,000 genes under the control of CpG island promoters where DNA methylation is rare. The
overall goal of this R21 project is to elucidate the mechanisms by which MeCP2 acts as a transcriptional
activator. The central hypothesis tested in this project is that MeCP2 activates many genes by novel dual
mechanisms through the direct interaction with CREB and through indirect interplay that prevents CREB1
from being sequestered in nonfunctional decoys. This research project will pursue the following specific
aims: 1) characterize the direct interaction between CREB and MeCP2 in vitro and 2) unravel the indirect
interplay between these proteins via DNA methylation. The research team will use biophysical and
biochemical approaches to examine the dual mechanisms. New knowledge about transactivation by MeCP2
will provide insight into epigenetic regulation in the brain and deepen our understanding of brain disorders.
For example, our biophysical characterizations of the CREB-MeCP2 interaction will provide new
perspectives for interpreting Rett syndrome mutations of MeCP2. The approaches established through this
project would potentially facilitate pharmacological screening of compounds that inhibit the CREB-MeCP2
interaction for drug addiction therapeutics in the future.

## Key facts

- **NIH application ID:** 9894858
- **Project number:** 5R21MH113098-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Junji Iwahara
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,631
- **Award type:** 5
- **Project period:** 2019-03-15 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894858

## Citation

> US National Institutes of Health, RePORTER application 9894858, Competitive interplay of neuronal transcription factors via DNA methylation (5R21MH113098-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894858. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*