Alterations to Genome Organisation in Stem Cells, Their Differentiation and Associated Diseases.

The organisation of the genome in its home, the cell nucleus, is reliant on a number of different aspects to establish, maintain and alter its functional non-random positioning. The genome is dispersed throughout a cell nucleus in specific chromosome territories which are further divided into topologically associated domains (TADs), where regions of the genome from different and the same chromosomes come together. This organisation is both controlled by DNA and chromatin epigenetic modification and the association of the genome with nuclear structures such as the nuclear lamina, the nucleolus and nuclear bodies and speckles. Indeed, sequences that are associated with the first two structures mentioned are termed lamina-associated domains (LADs) and nucleolar-associated domains (NADs), respectively. The modifications and nuclear structures that regulate genome function are altered through a cell's life from stem cell to differentiated cell through to reversible quiescence and irreversible senescence, and hence impacting on genome organisation, altering it to silence specific genes and permit others to be expressed in a controlled way in different cell types and cell cycle statuses. The structures and enzymes and thus the organisation of the genome can also be deleteriously affected, leading to disease and/or premature ageing.

Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells.

This study demonstrates, and confirms, that chromosome territory positioning is altered in primary senescent human dermal fibroblasts (HDFs). The chromosome territory positioning pattern is very similar to that found in HDFs made quiescent either by serum starvation or confluence; but not completely. A few chromosomes are found in different locations. One chromosome in particular stands out, chromosome 10, which is located in an intermediate location in young proliferating HDFs, but is found at the nuclear periphery in quiescent cells and in an opposing location of the nuclear interior in senescent HDFs. We have previously demonstrated that individual chromosome territories can be actively and rapidly relocated, with 15 min, after removal of serum from the culture media. These chromosome relocations require nuclear motor activity through the presence of nuclear myosin 1ß (NM1ß). We now also demonstrate rapid chromosome movement in HDFs after heat-shock at 42°C. Others have shown that heat shock genes are actively relocated using nuclear motor protein activity via actin or NM1ß (Khanna et al., 2014; Pradhan et al., 2020). However, this current study reveals, that in senescent HDFs, chromosomes can no longer be relocated to expected nuclear locations upon these two types of stimuli. This coincides with a entirely different organisation and distribution of NM1ß within senescent HDFs.