# The roles of Rett Syndrome protein MECP2 at gene regulatory elements

> **NIH MH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2026 · $641,828

## Abstract

Project Summary:
Rett Syndrome (RTT) is a progressive neurological disorder characterized by severe cognitive and motor
impairments caused primarily by mutations in MECP2. The molecular mechanisms by which disruption of
MECP2 gives rise to RTT remain unclear. MECP2 is known to bind to methylated DNA in the brain, regulating
the expression of neuronal genes. However, previous studies have shown complex patterns of gene
dysregulation in RTT that challenge this model, such that only a subset of genes appear to be regulated by
MECP2 binding to DNA methylation. We recently discovered that MECP2 preferentially binds to specific gene
enhancers that we named MECP2-Binding Hotspots (MBHs). Surprisingly, MECP2 binds to these MBHs
independently of DNA methylation, contrasting with its well-established role in binding methylated DNA. At
MBHs, MECP2 appears to act as a repressor of enhancer activity. Importantly, over 60% of genes
derepressed upon MECP2 deletion are associated with MBHs, suggesting that MBHs might be a major
mechanism by which MECP2 controls genes. Preliminary analyses indicate that MBHs, but not MECP2 bound
to methylated sites across the genome, are bound by histone deacetylase-containing nuclear receptor co-
repressor (NCOR) complex, suggesting that MBHs may repress enhancer activity by recruiting the NCOR
complex to enhancers. Taken together, our findings indicate a previously uncharacterized mechanism of
transcriptional regulation by MECP2. Moreover, these results implicate dysregulation of specific enhancers as
a possible mechanism underlying RTT. To gain insights into how MECP2 regulates genes and how
dysregulation of MECP2 leads to RTT, we propose to (1) define the interaction between MECP2 and MBHs,
and (2) elucidate the molecular mechanisms by which MBHs repress enhancers. This work has significant
implications for understanding the molecular basis of MECP2 function and the complex gene dysregulation
observed in RTT and will uncover new therapeutic targ

## Key facts

- **NIH application ID:** 11272760
- **Project number:** 1R01MH142417-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hume  Akahori Stroud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** MH
- **Fiscal year:** 2026
- **Award amount:** $641,828
- **Award type:** 1
- **Project period:** 2026-03-05T00:00:00 → 2030-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11272760

## Citation

> US National Institutes of Health, RePORTER application 11272760, The roles of Rett Syndrome protein MECP2 at gene regulatory elements (1R01MH142417-01). Retrieved via AI Analytics 2026-07-05 from https://api.ai-analytics.org/grant/nih/11272760. Licensed CC0.

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