Unveiling the molecular basis of chromatinopathies to delineate innovative therapeutic solutions

染色质病（CP）是一组罕见的遗传性疾病，其具有共同的临床特征以及致病性遗传改变，导致参与基因表达控制和3D染色质组织的染色质调节剂失活。在Chrom_Rare的框架内，我们将重点关注一组临床定义明确的CP，包括Kabuki综合征，CHARGE综合征，Rubinstein-Taybi综合征和科尔内利亚德兰格综合征。虽然这些CP的致病基因已被确定，但其在分子和功能水平上失活的后果尚未确定。CP的临床特征差异很大，这表明受影响的染色质调节因子的单倍不足的影响可能取决于表观遗传状态和/或与其他遗传和环境因素的相互作用。因此，了解CP的遗传和表观遗传决定因素代表了迫切的医学需求，因为这将最终促进新治疗方法的发展。我们的主要目标是建立一个部门内，跨学科的培训计划，将准备配备先进的理论，技术和计算技能的下一代研究人员，以研究染色质生物学的基本方面及其对CP的影响。与此同时，Chrom_Rare将设计新的策略，将分子发现转化为新的诊断和治疗方法，用于受CP影响的患者。为了能够理解染色质病的分子基础，我们的目标是开发多种疾病模型，概括CP的主要临床特征（WP 1），研究CP的遗传，表观遗传和拓扑决定因素（WP 2），并揭示适用于治疗干预（WP 3）的扰动调节电路。总体而言，Chrom_rare将解决尚未满足的社会经济、医疗和科学需求，以了解和可能治疗CP。

Chromatinopathies (CPs) are a group of rare genetic diseases, which share clinical features as well as causal genetic alterations, leading to the inactivation of chromatin regulators involved in gene expression control and 3D chromatin organization. Within the framework of Chrom_Rare, we will focus on a group of clinically well-defined CPs, including Kabuki Syndrome, CHARGE Syndrome, Rubinstein-Taybi Syndrome and Cornelia de Lange Syndrome. Although the causative genes for these CPs have been identified, the consequences of their inactivation both at the molecular and functional level, have not been defined. The clinical features of CPs vary widely, suggesting that the impact of the haploinsufficiency of the affected chromatin regulators could depend on the epigenetic state and/or interactions with additional genetic and environmental factors. Hence understanding the genetic and epigenetic determinants of CPs represent an immediate medical need, as this will ultimately facilitate reaching the development of new therapeutic approaches. Our main goal is to set-up an intra-sectoral, cross-disciplinary training programme that would prepare the next generation of researchers equipped with advanced theoretical, technical and computational skills to study fundamental aspects of chromatin biology and their impact on CPs. In parallel, Chrom_Rare will devise new strategies to translate the molecular findings into new diagnostic and therapeutic approaches for patients affected by CPs. To enable understanding the molecular basis of chromatinopathies, we aim at developing multiple disease models recapitulating the main clinical features of CPs (WP1), investigating the genetic, epigenetic and topological determinants of CPs (WP2) and uncovering perturbed regulatory circuitries suitable for therapeutic intervention (WP3). Overall Chrom_rare will address unmet socio-economic, medical and scientific needs, for the understanding and possible treatment for CPs.