Round half of the human genome consists of DNA fragments originating from historical viruses. These “transposable components” (TEs) are actually recognized to play varied roles in modulating gene expression and illness improvement. Now, a world crew led by KAUST researchers has proven {that a} widespread transposable ingredient referred to as LINE-1 RNA performs a constructive position in triggering bone restore, with potential functions in treating osteoporosis and lots of different ailments.
“As soon as termed ‘junk DNA,’ scientists thought that TEs have been irrelevant and even dangerous,” says analysis scientist Arianna Mangiavacchi at KAUST, who labored on the examine with college member Valerio Orlando and colleagues. “Nonetheless, many constructive roles for TEs are actually being uncovered, and our work on bone restore provides new data to this subject.”
Mangiavacchi and Orlando’s analysis focuses on getting old processes and the way the physique responds to environmental stressors over time. Scientists know TE ranges enhance as individuals age, however their roles in tissue well being are poorly understood. Earlier work by Mangiavacchi and colleagues advised a hyperlink between LINE-1 RNA exercise and bone well being, so the crew sought to confirm the mechanisms at play.
Firstly, the crew carried out sequencing experiments on mice with bone fractures and located that TEs, particularly LINE-1 RNA, have been upregulated for a brief time period following fracture.
Additional investigations confirmed that LINE-1 RNA activated a program of rigorously regulated irritation, which in flip induced a selected signaling pathway to restore the fracture.”
Arianna Mangiavacchi, analysis scientist, KAUST
The researchers then examined TEs in bone cells (osteoblasts) taken from postmenopausal ladies with osteoporosis and a wholesome management group. TEs, significantly LINEs, have been strongly upregulated in wholesome femurs with excessive bone density, whereas these with decrease bone density and osteoporosis exhibited low LINE expression.
“We added artificial LINE-1 RNA to those cell cultures, and the outcomes have been surprisingly clear,” says Mangiavacchi. “Osteoblasts handled with LINE-1 RNA displayed a particular phenotype the place the bone matrix fashioned abundantly and rapidly. Crucially, cells derived from osteoporotic sufferers have been rescued by the LINE-1 RNA therapy.”
“It seems the human physique co-opted viral TEs to set off an inflammatory response to break, thus kickstarting the innate immune system to restore bone and tissues. The so-called ‘darkish aspect’ of TEs was acquired intentionally into our genome, enabling us to adapt and be extra resilient,” says Orlando.
This discovery is protected by two patents, one licensed to biotech firm Altos Labs in California, and the opposite to the start-up firm RepeatEra, based by Orlando and Mangiavacchi, to take their pro-regenerative remedy to medical trials.
“We imagine this mechanism isn’t unique to bone, and so therapies primarily based on artificial LINE-1 RNA may have many functions, from corneal restore to skin-protective cosmetics,” says Mangiavacchi. “We’re excited to develop on these outcomes and perceive how TEs affect different cell sorts.”
Supply:
King Abdullah College of Science & Expertise (KAUST)
Journal reference:
Mangiavacchi, A., et al. (2024). LINE-1 RNA triggers matrix formation in bone cells by way of a PKR-mediated inflammatory response. The EMBO Journal. doi.org/10.1038/s44318-024-00143-z.
