# Transcriptional condensates, epigenetic editing and Rett Syndrome

> **NIH NIH R01** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2020 · $962,212

## Abstract

Abstract
Rett syndrome (RTT) is a postnatal progressive neurodevelopmental disorder associated with severe mental
disability and autism-like syndromes that manifests in girls during early childhood, and is caused by mutation of
the X-linked DNA binding protein MeCP2 (Methyl CpG-binding Protein 2). Mice carrying null alleles of Mecp2
closely mimic symptoms seen in patients and are faithful models of the disease. Importantly, development of
RTT-like symptoms can be slowed or even halted in the adult following correction of a mutant Mecp2 allele by
transgene-mediated MeCP2 expression.
 MeCP2 is one of the most abundant proteins in neurons, and most disease-causing mutations cluster in the
DNA binding domain (MBD) and in the transcription repression domain (TRD). However, the function of
MeCP2 remains enigmatic, with two major hypotheses having been proposed: (i) MeCP2 acts as repressor of
transcription or (ii) as an activator of transcription. Clearly, none of these proposed functions can fully explain
the complex phenotype of MeCP2 deficiency or overexpression leading to RTT or MECP2 Duplication
Syndrome. Based on our preliminary evidence we postulate that MeCP2’s primary function may be to
modulate the 3D chromosome architecture through condensate formation.
 Components of both euchromatin and heterochromatin can form phase-separated condensates, which
provide a mechanism to compartmentalize and concentrate biochemical reactions within cells and are
produced by liquid-liquid phase separation driven by intrinsically disordered regions (IDRs) of proteins. MeCP2
protein contains a large IDR and we have obtained preliminary evidence that MeCP2 is involved in phase-
separated heterochromatin condensates. Thus, beyond MeCP2’s role as a repressor or activator of gene
expression, the protein may have a much wider and more complex role in the cell physiology and disease.
 In this project we will define the contribution of MeCP2 to heterochromatic and euchromatic condensates in
normal and mutant neurons and analyze the effect of RTT causing mutations on LLPS. Our goal is to gain
insights into the function of MeCP2 as the basis for designing novel therapeutic approaches. Potential new
therapies based on this hypothesis will take time to develop into applications. To explore a more immediate
approach we will use epigenetic editing as a therapeutic tool to activate the inactive wt MECP2 allele located
on the inactive X chromosome. Most importantly, epigenetic editing will restore MeCP2 expression to exactly
wild type levels and thus avoid toxic consequences of MeCP2 overexpression. In contrast, other strategies
such as using vector-mediated MeCP2 transduction will invariably produce cells that overexpress MeCP2 and
thus will result in serious side effects as seen in patients with MECP2 duplication syndrome.

## Key facts

- **NIH application ID:** 10013304
- **Project number:** 5R01MH104610-21
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** RUDOLF JAENISCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $962,212
- **Award type:** 5
- **Project period:** 2014-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013304

## Citation

> US National Institutes of Health, RePORTER application 10013304, Transcriptional condensates, epigenetic editing and Rett Syndrome (5R01MH104610-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013304. Licensed CC0.

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