# Epigenetic regulation of alcohol tolerance and dependence by methyl CpG binding protein 2

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $362,813

## Abstract

Summary
 Long-term alterations in gene expression programs are believed to be key to the development and
progression of alcohol use disorder (AUD). The methyl CpG binding protein 2 (MeCP2), the causative gene of
Rett syndrome, is a protein that binds methylated DNA and, in turn, recruits transcriptional repressors resulting
in persistent down-regulation of gene expression. We observed that MeCP2 mutant mice with reduced
capacity to recruit transcriptional repressors exhibit a robust alcohol–related phenotype characterized by
heightened sensitivity to the sedative effects of alcohol, reduced alcohol intake in limited access 2-bottle choice
and lack of escalation of drinking after passive induction of dependence.
 Recent evidence indicates that MeCP2's primary function is to recruit a transcriptional repressor
complex at sites of methylated DNA through a discrete molecular domain. Importantly, MeCP2 has been found
to regulate a specific set of genes – or regulon – rather than broadly affecting gene expression levels, and we
found significant overlap between alcohol-regulated and MeCP2-regulated genes. Thus, in the present project
we will test the overarching hypothesis that MeCP2-regulated genes are key to alcohol's effects and to the
transition to escalated alcohol drinking in the setting of alcohol dependence. To test the sub-hypothesis that
recruitment of transcriptional repressors by MeCP2 is central to its effects on drinking, we will use MeCP2
mutant mice with reduced capacity to recruit transcriptional repressors in comparison with recently introduced
MeCP2 mutant mice with increased capacity to recruit transcriptional repressors, to provide optimal
perturbation of MeCP2 function for the analysis of MeCP2 regulated gene networks. To test the sub-hypothesis
that specific MeCP2 target genes and modulators are key to the transition to escalated drinking associated
with alcohol dependence, we will use a state of the art systems biology strategy that we recently validated for
the reconstruction and interrogation of genome-wide transcriptional interactomes from brain gene expression
profiles. This approach is centered on unbiased identification of transcriptional regulatory relationships from the
gene expression effects of the perturbations under study, rather than what is known from the literature or under
different sets of perturbations. Rather than identifying long lists of differentially expressed genes, this systems
biology strategy identifies and ranks a small number of genes driving the gene signatures associated with the
phenotype. Thus, specific mechanistic hypotheses on the role of MeCP2 in the effects of alcohol are obtained,
and will then be experimentally validated in paradigms of dependent and non-dependent alcohol drinking.
 Ultimately, the results of this study will advance our understanding of the molecular mechanisms behind
excessive alcohol drinking in the setting of dependence and will lay the rationale for the exploitation of ...

## Key facts

- **NIH application ID:** 10170163
- **Project number:** 5R01AA025012-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,813
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170163

## Citation

> US National Institutes of Health, RePORTER application 10170163, Epigenetic regulation of alcohol tolerance and dependence by methyl CpG binding protein 2 (5R01AA025012-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170163. Licensed CC0.

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