Architects of Forever

 28 February 2011   Research News

Architects of ForeverNuclear Architecture in Stem Cells

To see the sights of the nucleus and to marvel at its architectural forms is to understand the building plans of a biological cell. Those forms of complex configurations of DNA and histone proteins are the cellular programme writ large. They affect the environment of the cell, echoing the effect that our own architecture has on us. But trying to influence human social environments through architecture has been notoriously hit and miss; cells conversely are worlds whose cellular environment follows exactly from architecture – that of the chromatin inside the nucleus. Here, architecture is dynamic rather than static – its foundations not concrete but based on interactions between proteins and DNA; transient and plastic. Architectural surveyors of this strange place, Kelly Morris, Mita Chotalia and Ana Pombo of CSC Genome Function group, have assessed a decade of advances in our understanding of how nuclear architecture affects cellular environment in their review “Nuclear Architecture in Stem Cells”. So what is it about the nuclei of stem cells that makes them so different?

“Genome architecture is intimately related to genome function”
Histone proteins inside the nucleus are like modifiable scaffolding, allowing certain architectural features of chromatin to be altered and rendering DNA more or less accessible to transcriptional machinery. Like builders marking part of a building for demolition or improvement works with spray paint, certain enzymes tag chromatin with epigenetic marks, giving the instruction to either expose architectural forms – and the DNA they contain – or cover them up. Outward, exposed architecture influences its environment more than comparatively concealed constructions – the same for nuclei and buildings alike. In urban environments, not only builders but also gangs tag buildings, forming territories; in cells, genes and their relative positioning with respect to their chromosome territories may have important implications for gene expression. Their distribution is roughly the same in normal (somatic) cells and stem cells, indicating that many architectural features are formed very early on. Stem cells have more pluripotency genes located centrally in the nucleus – an important indicator of transcriptional activity, just as city centres are hives of social interaction and productivity in the human world.

Protruding into the nucleus from the inside of the envelope are lamina proteins, thin filaments that act like foundations for chromatin. In most cell types in our bodies, these supporting foundations fix the configuration of chromatin, like a building that cannot be modified because it has been granted heritage status. In stem cells, the architecture of the nucleus is not fixed: many lamina proteins are absent from the inside of the envelope. Chromatin inside is ‘hyper-mobile’, fluid, and therefore adaptable. Like the lifting of restrictions that have spurred the building of skyscrapers in the city of London, it is a state that encapsulates dynamism. But for most cells within organisms, and for most cities, this dynamic state – a reflection of nuclear and human architecture – occurs only at the beginning. In a cell, loss of mobility of chromatin is associated with loss of pluripotency, the feature of stem cells that allows them to become any cell in the body; like a city overprotected by conservation orders, it is unable to radically change.

ES cells are also more transcriptionally active; more productive. Elevated transcription of chromatin remodeling factors – in our urban analogy, an injection of cash, perhaps – help to maintain an open chromatin configuration. Another possibility is that hyperactive transcription could itself play a role in maintaining pluripotency by contributing to the plasticity of the genome. But this dynamic cellular city has another trick up its sleeve, practically engendering dynamism: bivalent histone marks. Some 2500 of these bimodal chemical modifications, simultaneously activating and repressing genes, occur in ES cells. The bimodality is resolved upon differentiation, leaving one mark – either activating or repressing – where there were two; the genomic equivalent of keeping its options open. Dynamism epitomised.

Morris, Chotalia and Pombo’s review spares the analogy with human architecture, and I hope they’ll forgive the more imaginative leaps made here. Nevertheless, they present the architecture of stem cells as an enthralling experience, even for a field still yet in its nascency:
“A common theme that is emerging is that the nuclear organisation of ES cells is less structured than differentiated cells,” say the authors. Furthermore, “the small number of studies that have probed the functional organisation of the ES cell nucleus already associate pluripotency with a highly dynamic genome that is reflected in a unique nuclear architecture.”

Morris KJ, Chotalia M, Pombo A (2010) Adv Exp Med Biol, 695:14-25