Cohesin and its regulators: from chromosome dynamics and nuclear architecture to human diseases

黏连蛋白是一种进化上保守的多蛋白复合物，属于染色体结构维持蛋白家族。它可以在拓扑学上捕获介导姐妹染色单体凝聚的DNA分子，这是精确染色体分离和DNA复制/修复的重要功能。最近发现，粘附素可以通过ATP酶依赖性的顺式DNA束缚活性（称为环挤出）产生和维持DNA环，这对于组织染色质结构和调节基因转录至关重要，因此被认为对细胞分化和发育很重要。然而，粘附素复合物实现这些关键细胞功能的分子机制仍有待阐明。编码粘着蛋白及其调节因子的基因突变导致一类发育障碍，统称为“粘着蛋白病”，并已在几种类型的癌症中发现。尽管如此，这些毁灭性的人类疾病的发病机制知之甚少。CohesiNet旨在通过一个高度创新的研究计划来回答粘着蛋白生物学领域的突出问题。该联盟将研究cohesin在染色体凝聚和环挤出过程中如何发挥作用的基本机制，确定cohesin功能的调控模块，并深入了解cohesin相关疾病的分子基础。这些雄心勃勃的目标将使用多学科假设驱动和探索性的方法来实现，同时促进整个欧洲联盟的学术和私营机构之间的沟通与合作文化。CohesiNet联盟将培训一个由10名博士生组成的团队，以解决这些科学问题，并获得增强其职业前景的技能，同时亲身体验开放科学的价值以及科学研究中包容性，透明度，可访问性和完整性的重要性。

Cohesin is an evolutionarily conserved multi-protein complex that belongs to the structural maintenance of chromosomes protein family. It can topologically entrap DNA molecules mediating sister chromatid cohesion, a function important for accurate chromosome segregation and DNA replication/repair. It has been recently discovered that cohesin can generate and maintain DNA loops by an ATPase-dependent in cis DNA tethering activity, called loop-extrusion, critical for organising chromatin architecture and regulating gene transcription, and as such thought to be important for cell differentiation and development. However, the molecular mechanisms by which the cohesin complex achieve these key cellular functions remain to be elucidated. Mutations in genes coding for cohesin and its regulators lead to a class of developmental disorders collectively called "cohesinopathies" and have been found in several types of cancer. Nonetheless, the pathogenesis of these devastating human diseases is poorly understood. CohesiNet aims to answer outstanding questions in the field of cohesin biology by a highly innovative research programme. This consortium will investigate fundamental mechanisms on how cohesin acts during chromosomal cohesion and loop extrusion, identify regulatory modules of cohesin functions and get insights into the molecular bases of cohesin-related diseases. These ambitious goals will be achieved using multi-disciplinary hypothesis-driven and exploratory approaches while promoting a culture of communication and cooperation among academic and private institutions across the European Union. A team of ten PhD students will be trained by the CohesiNet consortium to address these scientific questions and be empowered with skills that will enhance their career perspectives, while experiencing first-hand the value of Open Science and the importance of inclusion, transparency, accessibility and integrity in scientific research.