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

内聚蛋白是一种进化保守的多蛋白复合物，属于染色体结构维持蛋白家族。它可以从拓扑结构上捕获DNA分子，介导姐妹染色单体内聚，这是染色体精确分离和DNA复制/修复的重要功能。最近发现，黏结蛋白可以通过依赖atp酶的顺式DNA拴系活性产生和维持DNA环，称为环挤压，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，内聚蛋白复合体实现这些关键细胞功能的分子机制仍有待阐明。粘合蛋白及其调节因子编码基因的突变导致一类统称为“粘合病”的发育障碍，并已在几种类型的癌症中发现。尽管如此，人们对这些毁灭性人类疾病的发病机制知之甚少。内聚网旨在通过高度创新的研究计划回答内聚蛋白生物学领域的突出问题。该联盟将研究内聚蛋白在染色体内聚和环挤出过程中的基本机制，确定内聚蛋白功能的调控模块，并深入了解内聚蛋白相关疾病的分子基础。这些雄心勃勃的目标将通过多学科假设驱动和探索性方法来实现，同时促进整个欧盟学术和私人机构之间的交流与合作文化。一个由10名博士生组成的团队将接受CohesiNet联盟的培训，以解决这些科学问题，并获得提升职业前景的技能，同时亲身体验开放科学的价值以及科学研究中包容、透明、可及性和诚信的重要性。

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.