Rubinstein-Taybi Syndrome: Epigenetics, animals models, therapeutic trials

Rubinstein-Taybi syndrome (RSTS; OMIM #180849, OMIM #613684) is a severe embryonic neurodevelopmental disorder postnatally characterized by intellectual disability, typical facial dysmorphism, distal limbs abnormalities associated with many additional features.

The main challenge is to improve the intellectual and memory efficiency of these patients. This requires a better understanding of the mechanisms of long-term memory, which is very impaired in this syndrome.

CREBBP and EP300 are two paralogous genes which loss of function is involved in the determinism of RSTS type 1 and RSTS type 2, respectively.  These genes code for the CBP and p300 acetyltransferases mediating histone acetylation an epigenetic, chromatin remodeling mechanism acting in neuronal plasticity and cognition.


A deficit in KAT activity leads to inappropriate modifications of the chromatin structure and CBP and p300 mutations are associated with impaired neurodevelopment. To date no study bridging histone acetylation to deregulation of genes and neuronal dysfunction is currently available in RSTS.


Starting from RSTS patients’s cells, the GENEPI project aims to identify the biological pathways altered during normal and pathological differentiation of cortical and pyramidal neurons using correlations between differentially expressed genes, histone acetylation patterns and chromatin accessibility.


Defining specific epigenetic and transcriptomic signatures will pave the way to a better understanding of the pathophysiological basis of the syndrome, therapeutics targets and biomarkers.

In the longer term, this methodology could be applied to other chromatinopathies and allow therapeutic perspectives.

In this context, a biobank referenced to the Biological Resource Center has been created allowing the inclusion of any RSTS patient. To date, 15 patients have been included with a skin biopsy and a blood sample in a cohort gathering clinical and molecular data of more than 300 patients.

This project is part of a collaboration with the Genetics department of Bordeaux University Hospital and with Marseille Medical Genetics U1211 team of Dr. Frédérique Magdinier for its expertise in the study of epigenetic mechanisms in pathology and their induced pluripotent stem cell platform. It was made possible thanks to the close partnership with the RSTS French association (afsrt) and the sponsorship of the Rubinstein Taybi Foundation. The research group is also in the charge of the international guidelines for the disease.

– Epigenetics implication of CREBBP and EP300 during normal and abnormal differentiation of cortical and hippocampal neurons
– New therapeutic targets identification
– Histone deacetylase inhibitors trials in CBP mouse model
– Development of phosphodiesterase 4D (PDE4-D) inhibitors, regarding new clinical trials


Contributing Members

D. Lacombe
P. Fergelot
B. Arveiler
J. Van-Gils

National and International Collaborations

Pr. Raoul Hennekam. [Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands]
Dr. Valérie Lallemand-Mezger. [Epigenetics and Cell Fate, UMR7216, University Paris Diderot, 75013 PARIS]
Dr. Angel Barco. [Instituto de Neurociencias (UMH-CSIC), Alicante, Spain]
Dr. Aline Marighetto. [Physiopathologie de la mémoire déclarative, INSERM U1215, Neurocentre Magendie, Bordeaux]
Pr. Luc Grislain. [Dept. Pharmacologie, Université de Bordeaux]
Pr. Nicolas Levy. [Université de Marseille]
Dr. Frédérique Magdinier. [Université de Marseille]
Pr. David Geneviève. [Service Génétique, Université de Montpellier]