Ignite Creation Date:
2024-05-06 @ 1:46 PM
Last Modification Date:
2024-10-26 @ 1:20 PM
Study NCT ID:
NCT04122742
Status:
RECRUITING
Last Update Posted:
2024-01-17
First Post:
2019-10-09
Brief Title:
Diagnosis of RSTS Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP and EP300 Variants
Sponsor:
University Hospital Bordeaux
Organization:
University Hospital Bordeaux
Study Overview
Official Title:
Diagnosis of RSTS Identification of the Acetylation Profiles as Epigenetic Markers for Assessing Causality of CREBBP and EP300 Variants
Status:
RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GENEPI
Brief Summary:
Rubinstein-Taybi syndrome RSTS is a rare and severe congenital developmental disorder characterized by congenital anomalies and intellectual disability with a long term memory deficit The main challenge is to improve the intellectual and memory efficiency of these patients CREBBP and EP300 are the two genes known to cause RSTS Both paralogs play a major role in chromatin remodeling and encode for transcriptional co-activators interacting with many proteins
The aim of this pilot study is to characterize the histone acetylation profiles in order to identify specific acetylation markers during normal and pathological neuronal differentiation of cortical and pyramidal neurons in RSTS
The aim of this pilot study is to characterize the histone acetylation profiles in order to identify specific acetylation markers during normal and pathological neuronal differentiation of cortical and pyramidal neurons in RSTS
Detailed Description:
CREBBP and EP300 are the two paralog genes associated with RSTS determinism and code for CBP and p300 respectively These proteins are transcriptional coactivators that possess a catalytic lysine acetyl transferase KAT domain involved in the acetylation of lysine residues of histones but also other proteins CBP and p300 promote transcription by creating a chromatin environment that is favorable for gene expression and by linking different transcription factors to each other They thus orchestrate the regulation of the transcription machinery from the basal promoter to the enhancers of the target genes
RSTS is considered a genetic model of neurodevelopmental anomaly with an epigenetic component
Histone acetylation is one of the major post-translational modifications PTMs of these proteins that provide for the formation and control of chromatin structure When differentiating embryonic cells this modification plays a key role in transcriptional activation
The mouse models of RSTS have made the link between the modulation of histone acetylation and the formation of memory by showing their key role in neuronal plasticity However no data exists on the acetylation of histones in the neurons of RSTS patients Furthermore in humans the molecular pathways impacted by these alterations during neurodevelopment are not specified especially in the pyramidal neurons which are the precursors of hippocampal neurons involved in the encoding and storage of memory
In RSTS a loss of CBP function results in a deficit in KAT activity which is responsible for altering histone acetylation leading to inappropriate changes in chromatin structure The consequence of a mutation is a result of a deregulation of the activity of genes involved in development No neuronal level studies are currently available on the functional link between histone acetylation and deregulated genes in the RSTS
In this project investigators will identify target genes whose epigenetic regulation is mediated by histone acetylation More specifically the study will focus on chromatin dynamics during normal and pathological neuronal differentiation of cortical and pyramidal neurons Investigators will determine among the CBP-dependent histone markers those that are modified in RSTS patients cells and the loci they control In parallel investigators will define genes whose neuronal expression is altered in RSTS patients
The integration of all these data will allow us to specify which genes are deregulated during neuronal differentiation as a consequence of CBP lysine acetyltransferase function loss
RSTS is considered a genetic model of neurodevelopmental anomaly with an epigenetic component
Histone acetylation is one of the major post-translational modifications PTMs of these proteins that provide for the formation and control of chromatin structure When differentiating embryonic cells this modification plays a key role in transcriptional activation
The mouse models of RSTS have made the link between the modulation of histone acetylation and the formation of memory by showing their key role in neuronal plasticity However no data exists on the acetylation of histones in the neurons of RSTS patients Furthermore in humans the molecular pathways impacted by these alterations during neurodevelopment are not specified especially in the pyramidal neurons which are the precursors of hippocampal neurons involved in the encoding and storage of memory
In RSTS a loss of CBP function results in a deficit in KAT activity which is responsible for altering histone acetylation leading to inappropriate changes in chromatin structure The consequence of a mutation is a result of a deregulation of the activity of genes involved in development No neuronal level studies are currently available on the functional link between histone acetylation and deregulated genes in the RSTS
In this project investigators will identify target genes whose epigenetic regulation is mediated by histone acetylation More specifically the study will focus on chromatin dynamics during normal and pathological neuronal differentiation of cortical and pyramidal neurons Investigators will determine among the CBP-dependent histone markers those that are modified in RSTS patients cells and the loci they control In parallel investigators will define genes whose neuronal expression is altered in RSTS patients
The integration of all these data will allow us to specify which genes are deregulated during neuronal differentiation as a consequence of CBP lysine acetyltransferase function loss
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None