The Shifting Genome: How Shape Controls Your Biology

How does genomic structure dictate function?

The human genome is 2 metres long and yet can be packed into a space of between 5-10 micrometres. How does biology accomplish this? DNA is packaged and organised into all kinds of shapes, but while the code is certainly important, scientists are now realising just how central the role structure plays in gene expression and regulation. 

Your DNA spends most of its time tightly packaged up, wound around proteins and organised into something called chromatin (essentially DNA and its packaging proteins). This chromatin forms each of your 46 chromosomes and these masses of folds are modulated by other proteins, pinned to the nucleus and kept from tangling up - forming an overall 3-D configuration. We're now coming to realise this mobile, fluid shape actually influences gene activity and that the structure itself plays a dominant role in shaping exactly what bits of your DNA are being read - opening up and closing specific regions.

 

DNA is packaged and stored in complex, moving shapes 

“It is conceivable that every nuclear process has an element of structure in it. It’s surprising, in fact, that we studied DNA for so long and yet we still have relatively little understanding of its 3-D architecture.”

 

 

The 3-D structure of DNA in every nucleus is extremely important: telomere caps protect your chromosomes from unraveling and varying organisation can affect your DNA - creating stability or rendering it vulnerable to damage. As we age, genomic stability in many cells starts to decline and organisation can become dysregulated. Changes in chromatin structure have been linked to a number of diseases, cancer and aging itself. Understanding how different genomic architecture influences how your genome is transcribed could therefore be key in improving our ability to regulate certain genes. 

 

Image courtesy of Broad Communications

 

 

'There are whole classes of diseases where people are going to have aberrations of where their loops are'

 

 

 

 

 

A young girl with progeria (left). A deformed cell nucleus present in the condition (right, bottom)

In the inherited disease progeria (also known as Hutchinson–Gilford progeria syndrome) patients exhibit many aspects of aging in childhood and rarely live past 20. Progeria is caused by a deficient nuclear lamina - the lining of the nucleus which helps organise and stabilise the structure of the genome. 

 

 

 

Due to advances in technology, scientists are now looking closer at the incredible structures that shift inside the nucleus, and are trying to establish what the complex folds actually mean and how they influence transcription. Because this 3-D conformation changes and adapts with time, understanding requires 4-D modelling - examining how the shape changes with time. In 2014 the National Institutes of Health launched the 5 year 4-D Nucleome Program, which aims to map this spatial organization and understand the role nuclear architecture plays in health. 

 

Chromosomes interact in a spaghetti-like organised tangle. Credit: Takashi Nagano and Tim Stevens 

 

'A genome is more than information written in DNA. It’s an interesting physical object'

 

 

 

 

We now know that the various loops and forms the genome creates can interact and communicate with each other even from a distance - enhancing or inhibiting gene expression. Epigenetic regulation and these conformational differences are what make cells specialised.  Every cell should have the same genetic code but most of it is silenced at any specific moment. Understanding how this process works in detail is essential if we want effective regenerative medicine. 

A great deal about gene expression and genomic stability is still unknown, and there is hope that with greater understanding, this research could aid work on fields like stem cells and reprogramming. Each healthy, fertilised egg gets a fresh slate - the majority of epigenetic alterations being essentially wiped clean. Understanding exactly what happens along the way from germ cells to the embryo could help us develop technologies that can rewind the cellular clock and create better stem cell populations from our own adult cells. Chromosomes also constantly shift and change in response to stimuli or prompts like circadian rhythms, so learning more about the intricacies of these processes could produce more advanced gene regulating technologies. 

 

“I feel like in a small way, 3-D genome maps are eloquent in that way. Once you have that resolution…you can just read biology.”

 

Read more at Science News and The Scientist