Genome compartmentalization by LAP2a and lamins

The human genome is localized in the cell nucleus. It contains the master plan for the generation of cell types and tissues. This information is stored in around 30.000 genes within the genome, and a combination of specific genes has to be activated to produce certain tissue, while genes not needed in this tissue have to be kept inactive. Thus, a correct regulation of genes is essential for the development and repair of all tissues in the human body. Gene regulation is accomplished at different levels. Firstly, nuclear complexes bind to genes and activate or deactivate them directly. Secondly, the packing of the genome into specific subregions as well as the specific location of genes within the three-dimensional space of the cell nucleus also contributes to gene regulation. While the first mechanism is well understood, the way how spatial location of genes within the nucleus affects gene expression is poorly understood. Our project is centered around this latter important open question and focuses on nuclear molecules that contribute to genome organization, called lamins. Lamins come in two flavors. At the nuclear periphery they form a filamentous network that tethers densely packed regions of the genome to the nuclear periphery, thereby ensuring that genes in these regions remain inactive. We have previously reported another pool of lamins, which localizes in the center of the nucleus and binds, together with its interaction partner lamin-associated protein 2alpha (LAP2a), to less-densely packed subregions of the genome with many active genes. Deletion of LAP2a or lamins impairs gene regulation and tissue formation, implying that the binding of lamins to the genome in the center of the nucleus is important for correct gene regulation. Similarly, mutations in lamins or LAP2a are linked to human diseases, which affect multiple tissues and organs, including skeletal muscle, heart and fat tissue. In this project we aim at identifying regions in the genome, where LAP2a and lamins bind to at high resolution and want to understand, how lamin binding is directed to these genomic subregions. We will test, whether specific properties of lamins or specific features in the genomic regions define these interactions. We hypothesize that LAP2a and lamins form highly dynamic assemblies on chromatin in the center of the nucleus that affect gene expression. We will study, if and how these lamin assemblies may mediate cross-link formation between different genomic subregions, thereby contributing to the three-dimensional organization of the genome. In addition, we will test the possibility that lamin compartments may facilitate the recruitment of molecules required for the activation or deactivation of genes. Overall, our study is expected to provide a major conceptual advance in our understanding of lamin function in genome organization and shed light on the poorly understood complex roles of lamins in gene regulation of healthy and diseased tissues.