Diagnosis of Rubinstein-Taybi syndrome: definition of acetylation profiles as epigenetic markers for assessing causality of CREBBP/EP300 variants – EPI-RUBI

Epigenetic modifications of histones such as acetylation can modify chromatin structure, modulating gene expression. This acetylation plays a key role in transcriptional regulation during embryonic development. The CBP and p300 proteins are transcriptional co-factors belonging to the KAT3 family of Histone Acetyl Transferases and are encoded respectively by the genes CREBBP and EP300, which are involved in the determinism of Rubinstein-Taybi syndrome (RSTS). This rare neurodevelopmental disorder is characterized by intellectual disability and typical abnormalities of the face and extremities and numerous other malformations. RSTS represents a model disease for the study in human pathology of epigenetic modifications. Mice model studies have shown the impact of a loss of CBP and p300 function during neurodevelopment on storage and encoding of memory. In humans, the molecular pathways affected are not yet specified. Our rare disease reference center is the national reference for the diagnosis of RSTS, with a cohort of more than 300 patients whose phenotype and causal mutation are characterized. We propose to characterize the acetylation profiles in these patients by comparing them to controls. This study will be conducted using induced pluripotent stem cells (IPSc) derived from fibroblasts of patients mutated for CREBBP or EP300 and healthy controls and then differentiated into cortical and pyramidal neurons. The analysis will include acetylome analysis by LC-MS supplemented with ATAC-seq to validate the histones targeted of acetylation and RNA-seq to identify molecular pathways impacted during neurodevelopment. The objective is to characterize the specific acetylation profiles of CREBBP/EP300 during neuronal differentiation to develop functional tests adapted in the context of diagnosis.