CRISPR reveals truth about ancient viral DNA and rare muscular dystrophy

Ancient viral DNA sequences in the mouse genome may offer insight into a severe muscle-wasting disease in humans.

Transposable elements are stretches of DNA that constitute eight to ten percent of the mammalian genome. Previously considered 'junk DNA', they originate from remnants of viral DNA left in the genomes of our ancestors by infections millions of years ago. New research investigated an element called MERVL and an associated protein called Dux, which are essential for kick-starting embryo development (see BioNews 1225 and 1274). However, Dux is toxic to cells if it remains active for too long, and because it activates MERVL, previous research was unable to determine if the viral DNA itself was contributing to this toxicity, or if the damage was caused solely by the Dux protein.

'By being able to compare what's happening in these different contexts, we can see that transposable elements in this case aren't the bad guys,' said Dr Paul Chammas, formerly of the MRC Laboratory of Medical Sciences (LMS) in London, and co-lead author of the research published in Science Advances. 'And we've successfully started to unpick some of the different roles different parts of the network play in early development'.

To understand these roles, the team used CRISPR activation (CRISPRa). Unlike the better-known CRISPR/Cas9, which cuts DNA, CRISPRa boosts the activity of specific genes without changing the underlying sequence. By selectively switching on MERVL in mouse embryonic stem cells, they found it was sufficient to drive key features of development without causing toxicity.

Conversely, when they examined Dux, they found its toxicity is not linked to the viral DNA. Instead, they demonstrated that while Dux activates MERVL, it also activates Noxa, a protein that triggers cell death. By removing Noxa, the researchers showed that the cell damage was significantly reduced.

This distinction identifies a vital link to human disease. The human version of Dux, called DUX4, drives facioscapulohumeral muscular dystrophy: an incurable condition causing progressive muscle weakness. The researchers found that, as in mice, DUX4 elevates levels of NOXA in human cells. Patient samples with this severe inherited disease showed the highest levels of NOXA, suggesting that drugs blocking this protein could prevent muscle cell death.

'More broadly, facioscapulohumeral muscular dystrophy is a complex disease – even though all cells of a patient have the genetic changes that cause it, only a subset of cells activate DUX4,' said lead author Dr Michelle Percharde, head of the Chromatin and Development group at MRC LMS.

Dr Percharde concluded that future work will explore what triggers DUX4 activation specifically in human muscle cells and how this compares to its regulation during early development.