Jumping genes help make neurons in a dish

March 26, 2020

The process of making functional brain cells in a lab dish requires the precise activation of selfish genetic elements known as LINE-1 (L1) retrotransposons. The finding, from researchers at KAUST, could lead to safer and more effective regenerative therapies for Parkinson's disease and other brain conditions.

The genomes of humans, mice and other mammals have hundreds of thousands of L1 elements. Most are inactive, yet some retain the ability to make copies of themselves and jump into different segments of DNA, with impacts on gene regulation that can be both harmful and beneficial. Sometimes, the jumping genes can trigger disease. In early brain development, however, L1 activity is needed for neurons to form properly--although the reason had been unclear.

To address this question, Valerio Orlando and colleagues turned to a cellular model of neuronal development. Working with scientists in Italy, they engineered skin cells taken from mouse embryos to express various "reprogramming factors'" that converted them into dopamine-producing neurons, similar to those found in the substantia nigra, a small structure located deep in the brain. In the process, the researchers observed L1 activation.

They treated the cells with two kinds of drugs that block L1 dynamics. Both treatments dramatically impaired the efficiency of cell conversion, demonstrating that "activation is required for successful reprogramming of skin cells into neuronal cells," according to Francesco Della Valle, a postdoc in Orlando's lab group, and the first author of the new study.

The researchers then sequenced all the DNA inside the cells, both before and after their conversion, to determine where the L1 elements had newly inserted themselves into the genome. They found insertional hotspots around the genes involved in neuronal lineage commitment and neuron function. Consequently, the DNA at these sites was less densely packaged, allowing for higher levels of relevant gene expression.

"Our work boosts the concept that repetitive elements play an important, unprecedented role in cell differentiation and tissue specific developmental programs," Della Valle says.

Those insights could prove invaluable as researchers design new kinds of cell therapies to replace the dopamine-producing neurons lost in people with Parkinson's disease and related disorders. "Aberrant L1 activity could threaten the viability or safety of any such product," notes Della Valle, "while optimizing L1 function could enhance the manufacturing and consistency of this type of regenerative treatment."
-end-


King Abdullah University of Science & Technology (KAUST)

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.