Periodic Reporting for period 1 - Chrom_rare (Unveiling the molecular basis of chromatinopathies to delineate innovative therapeutic solutions)
Periodo di rendicontazione: 2023-01-01 al 2024-12-31
Understanding and Addressing Chromatinopathies: A Step Toward Better Diagnosis and Treatment
Chromatinopathies (CPs) are a group of rare genetic disorders caused by mutations in genes that regulate how DNA is organized and accessed within our cells. These mutations disrupt gene function, leading to a range of clinical symptoms shared across different CPs. Some well-known conditions within this group include Kabuki Syndrome (KS), CHARGE Syndrome (CS), Rubinstein-Taybi Syndrome (RTS), and Cornelia de Lange Syndrome (CdLS).
Although scientists have identified the genes responsible for these disorders, we still lack a full understanding of how their inactivation affects cellular functions and leads to disease. The symptoms of CPs vary significantly from patient to patient, suggesting that genetic mutations alone may not explain the full picture. Other factors—such as epigenetic changes (which influence how genes are turned on or off) and interactions with environmental or additional genetic factors—could play a role in disease development and severity.
This knowledge gap presents an urgent medical need: understanding the genetic and epigenetic mechanisms behind CPs is crucial for developing better diagnostic tools and potential treatments.
Through Chrom_Rare, we aim to bridge this gap by training the next generation of researchers with expertise in chromatin biology, advanced molecular techniques, and computational analysis. Our project will also work to translate scientific discoveries into practical solutions for patients.
Our approach includes:
Developing disease models that mimic key clinical features of CPs (WP1)
Investigating the genetic, epigenetic, and structural factors contributing to CPs (WP2)
Identifying disrupted regulatory mechanisms that could be targeted for therapy (WP3)
By addressing these critical scientific, medical, and socio-economic challenges, Chrom_Rare strives to pave the way for better understanding and treatment of chromatinopathies, ultimately improving the lives of affected individuals and their families.
Chromatinopathies (CPs) are a group of rare genetic disorders caused by mutations in genes that regulate how DNA is organized and accessed within our cells. These mutations disrupt gene function, leading to a range of clinical symptoms shared across different CPs. Some well-known conditions within this group include Kabuki Syndrome (KS), CHARGE Syndrome (CS), Rubinstein-Taybi Syndrome (RTS), and Cornelia de Lange Syndrome (CdLS).
Although scientists have identified the genes responsible for these disorders, we still lack a full understanding of how their inactivation affects cellular functions and leads to disease. The symptoms of CPs vary significantly from patient to patient, suggesting that genetic mutations alone may not explain the full picture. Other factors—such as epigenetic changes (which influence how genes are turned on or off) and interactions with environmental or additional genetic factors—could play a role in disease development and severity.
This knowledge gap presents an urgent medical need: understanding the genetic and epigenetic mechanisms behind CPs is crucial for developing better diagnostic tools and potential treatments.
Through Chrom_Rare, we aim to bridge this gap by training the next generation of researchers with expertise in chromatin biology, advanced molecular techniques, and computational analysis. Our project will also work to translate scientific discoveries into practical solutions for patients.
Our approach includes:
Developing disease models that mimic key clinical features of CPs (WP1)
Investigating the genetic, epigenetic, and structural factors contributing to CPs (WP2)
Identifying disrupted regulatory mechanisms that could be targeted for therapy (WP3)
By addressing these critical scientific, medical, and socio-economic challenges, Chrom_Rare strives to pave the way for better understanding and treatment of chromatinopathies, ultimately improving the lives of affected individuals and their families.
Background and Motivation
Chromatinopathies (CPs) are a group of rare genetic disorders caused by mutations in genes that regulate chromatin—the complex structure that organizes DNA in cells. These mutations disrupt gene expression and genome folding, leading to a wide range of symptoms. Interestingly, even individuals with the same mutation can experience different levels of severity, suggesting that additional factors—such as epigenetics (chemical modifications influencing gene activity) and environmental interactions—play a key role.
Because these conditions currently have no targeted treatments, understanding the genetic and epigenetic mechanisms behind CPs is a critical medical need. By uncovering these mechanisms, researchers can develop better diagnostic tools and explore potential therapeutic strategies.
Objectives and Research Approach
The Chrom_Rare project aims to bridge this knowledge gap by developing innovative research strategies through three main work packages (WPs):
During this first RP the project has progressed in the following manner:
WP1: Developing Disease Models to Study CPs
To better understand CPs, researchers are creating laboratory models that replicate the genetic causes and clinical features of these disorders. Ongoing efforts have included:
Expanding patient-derived biobanks with fibroblast and lymphoblastoid cell samples (UNINA, CHUM).
Using CRISPR/Cas9 gene editing to introduce CP-associated mutations in stem cells (UNITN).
Generating induced pluripotent stem cells (hiPSCs) from patient fibroblasts to study different tissues, particularly neurons (UNINA, CHUM, MAN).
Developing in vivo models, such as zebrafish models for Kabuki Syndrome (CHUM) and a degron-based system to mimic Cornelia de Lange Syndrome (CSIC).
WP2: Investigating the Role of Epigenetics and 3D Genome Organization
This work package focuses on understanding how changes in chromatin structure contribute to CP symptoms. Key research activities have included:
Profiling chromatin states in patient-derived cells to detect epigenetic modifications (UM, UNINA).
Analyzing gene expression changes using RNA sequencing (UM).
Developing computational tools to integrate chromatin and transcriptomic data, revealing how 3D genome organization affects CPs (GP).
Studying protein interactions at the chromatin level, using advanced labeling techniques (RU, UNITN).
WP3: Identifying and Testing Therapeutic Strategies
The ultimate goal is to develop targeted treatments for CPs by identifying and correcting molecular dysfunctions. Key efforts have included:
Characterizing CP-affected neurons to identify common molecular defects (MAN).
Developing biosensors to measure nuclear mechanical properties and test drug responses (UNITN).
Identifying druggable targets using genome-wide epigenetic data (GP).
Investigating immune system dysfunctions in CP patients by studying immune cells derived from hiPSCs and primary lymphocytes (UM, CHUM).
Impact and Future Directions
By integrating cutting-edge genetic, epigenetic, and computational approaches, Chrom_Rare aims to uncover the molecular basis of CPs and pave the way for new diagnostic and therapeutic strategies. This project not only advances scientific understanding but also offers hope for patients and families affected by these rare disorders.
Chromatinopathies (CPs) are a group of rare genetic disorders caused by mutations in genes that regulate chromatin—the complex structure that organizes DNA in cells. These mutations disrupt gene expression and genome folding, leading to a wide range of symptoms. Interestingly, even individuals with the same mutation can experience different levels of severity, suggesting that additional factors—such as epigenetics (chemical modifications influencing gene activity) and environmental interactions—play a key role.
Because these conditions currently have no targeted treatments, understanding the genetic and epigenetic mechanisms behind CPs is a critical medical need. By uncovering these mechanisms, researchers can develop better diagnostic tools and explore potential therapeutic strategies.
Objectives and Research Approach
The Chrom_Rare project aims to bridge this knowledge gap by developing innovative research strategies through three main work packages (WPs):
During this first RP the project has progressed in the following manner:
WP1: Developing Disease Models to Study CPs
To better understand CPs, researchers are creating laboratory models that replicate the genetic causes and clinical features of these disorders. Ongoing efforts have included:
Expanding patient-derived biobanks with fibroblast and lymphoblastoid cell samples (UNINA, CHUM).
Using CRISPR/Cas9 gene editing to introduce CP-associated mutations in stem cells (UNITN).
Generating induced pluripotent stem cells (hiPSCs) from patient fibroblasts to study different tissues, particularly neurons (UNINA, CHUM, MAN).
Developing in vivo models, such as zebrafish models for Kabuki Syndrome (CHUM) and a degron-based system to mimic Cornelia de Lange Syndrome (CSIC).
WP2: Investigating the Role of Epigenetics and 3D Genome Organization
This work package focuses on understanding how changes in chromatin structure contribute to CP symptoms. Key research activities have included:
Profiling chromatin states in patient-derived cells to detect epigenetic modifications (UM, UNINA).
Analyzing gene expression changes using RNA sequencing (UM).
Developing computational tools to integrate chromatin and transcriptomic data, revealing how 3D genome organization affects CPs (GP).
Studying protein interactions at the chromatin level, using advanced labeling techniques (RU, UNITN).
WP3: Identifying and Testing Therapeutic Strategies
The ultimate goal is to develop targeted treatments for CPs by identifying and correcting molecular dysfunctions. Key efforts have included:
Characterizing CP-affected neurons to identify common molecular defects (MAN).
Developing biosensors to measure nuclear mechanical properties and test drug responses (UNITN).
Identifying druggable targets using genome-wide epigenetic data (GP).
Investigating immune system dysfunctions in CP patients by studying immune cells derived from hiPSCs and primary lymphocytes (UM, CHUM).
Impact and Future Directions
By integrating cutting-edge genetic, epigenetic, and computational approaches, Chrom_Rare aims to uncover the molecular basis of CPs and pave the way for new diagnostic and therapeutic strategies. This project not only advances scientific understanding but also offers hope for patients and families affected by these rare disorders.
Impact and Future Directions
By integrating cutting-edge genetic, epigenetic, and computational approaches, Chrom_Rare aims to uncover the molecular basis of CPs and pave the way for new diagnostic and therapeutic strategies. This project not only advances scientific understanding but also offers hope for patients and families affected by these rare disorders.
By integrating cutting-edge genetic, epigenetic, and computational approaches, Chrom_Rare aims to uncover the molecular basis of CPs and pave the way for new diagnostic and therapeutic strategies. This project not only advances scientific understanding but also offers hope for patients and families affected by these rare disorders.