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

Abstract

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.

Keywords: Cellular senescence; Childhood leukaemia; Colorectal cancer; Differentiation; Embryogenesis; Genome organisation; Hutchinson-Gilford progeria syndrome; Lamina-associated domains; Nucleolar-associated domains; Stem cells; Topologically associated domains.