Chromatin Position Affects Gene Expression

Gene expression is regulated at multiple levels, starting at transcription initiation and moving all the way through to the translation of mature mRNA into a functional protein.  However, not all of the enzymes required for gene expression and regulation are distributed equally in the nucleus. Instead, they are limited to spatially defined foci.  This results in non-overlapping "territories" in the nucleus, with specific biochemical activity.  For example, the genes coding for ribosomal RNA present on chromosomes 13,14,15, 21 and 22, also known as nucleolar organizer regions, are clustered in the nucleolus – the cell's ribosome formation site.  This means that chromatin can be repositioned to such functionally distinct foci for coordinated gene expression and regulation.  However, chromatin can also extend outside its territory, forming an extended loop that can alter the gene expression pattern. For instance, the human gene CFTR is located at the nuclear periphery in the cells where it is silent. However, in cells where the gene is expressed, the chromatin containing this region is repositioned towards the interior. Most eukaryotic cells have multiple chromatin fibers with distinct length and compaction ratio. Therefore, the chromatin positioning also depends on the physical constraints of its packaging inside the nucleus.  In cells with spherical nuclei such as lymphocytes, the chromatin is radially positioned with actively expressed genes towards the interior and the repressed genes at the periphery.  In cells with nonspherical nuclei, such as fibroblasts, the shorter chromatin fibers tend to occupy the internal position while the longer chromatin fibers are positioned at the nucleus' periphery. Chromatin repositioning is also associated with different types of cancers, where altered gene expression patterns due to chromatin repositioning can lead to tumor formation. For example, the repositioning of chromosome 18 from the nuclear periphery to the interior is observed in the development of cervical and colon carcinomas.