Artificial genes help understand how cells learn their location in the body

Researchers at New York University have discovered artificial Hox genes – which plan and direct where cells go to develop tissues or organs – using new synthetic DNA technology and genomic engineering in stem cells.

their findings, published in Scienceconfirm how clusters of Hox genes help cells learn and remember where they are in the body.

Hox genes as architects of the body

Nearly all animals — from humans to birds to fish — have an anterior-posterior axis, or a line that runs from head to tail. During development, Hox genes act as architects, setting the plan for where cells go along the axis, as well as what body parts they make up. Hox genes ensure that organs and tissues develop in the right place, form the thorax or place wings in the right anatomical positions.

if Hox genes fail due to misregulation or mutation, cells can be lost and play a role in some cancers, birth defects and miscarriages.

“I don’t think we can understand development or disease without understanding” Hox genes,” said Esteban Mazzonicassociate professor of biology at NYU and the study’s co-senior author.

Despite their importance for development, Hox genes are challenging to study. They are tightly organized in clusters, with only Hox genes in the piece of DNA where they are found and no other genes around it (what scientists call a “gene desert”). And while many parts of the genome contain repetitive elements, Hox clusters do not have such repeats. These factors make them unique, but difficult to study with conventional gene editing without affecting the neighboring ones Hox genes.

Starting over with synthetic DNA

Can scientists create artificial ones? Hox genes to better study them, rather than relying on gene editing?

“We are very good at reading the genome, or sequencing DNA. And thanks to CRISPR, we can make small adjustments in the genome. But we’re still not good at writing from scratch,” explains Mazzoni. “Writing or building new pieces of the genome could help us test for adequacy — in this case, find out what the smallest unit of the genome is needed to let a cell know where it is in the body.” .”

Mazzoni works together Jef Boeke, director of the Institute of System Genetics at NYU Grossman School of Medicine, who is known for his work synthesizing a synthetic yeast genome. Boeke’s lab wanted to translate this technology into mammalian cells.

Graduate student Sudarshan Pinglay made long strands of synthetic DNA in Boeke’s lab by copying DNA from the Hox genes from rats. The researchers then delivered the DNA to a precise location in pluripotent stem cells from mice. By using the different species, the researchers were able to distinguish between the synthetic rat DNA and the natural cells of mice.

“Dr. Richard Feynman once said, “What I cannot create, I do not understand.” We are now one big step closer to understanding Hox‘, says Boeke, who is also a professor of biochemistry and molecular pharmacology at NYU Grossman and the co-senior author of the study.

Studying Hox clusters

With the artificial Hox DNA in mouse stem cells, the researchers were now able to investigate how Hox genes help cells learn and remember where they are. In mammals, Hox clusters are surrounded by regulatory regions that determine how the Hox genes are activated. It was not known whether the cluster alone or the cluster plus other elements was necessary for the cells to learn and remember where they are.

The researchers found that only these gene-dense clusters contain all the information cells need to decode and remember a positional signal. This suggests that the compact nature of Hox clusters is what helps cells learn their location, confirming a long-standing hypothesis about Hox genes that were previously difficult to test.

The creation of synthetic DNA and artificial Hox genes paves the way for future research on animal development and human disease.

“Different species have different structures and shapes, much of which depends on how Hox clusters are expressed. For example, a snake is a long thorax with no limbs while a skate has no thorax and is only limbs. A better understanding of Hox clusters can help us understand how these systems are adapted and adapted to make different animals,” Mazzoni said.

“More generally, this synthetic DNA technology, for which we’ve built a kind of factory, will be useful for studying diseases that are genomically complicated, and now we have a method to produce much more accurate models for them,” Boeke says.

Reference: Pinlay S, Bulajić M, Rahe DP, et al. Synthetic regulatory reconstitution reveals principles of Hox cluster regulation in mammals. Science† 2022;377(6601):eabk2820. bye: 10.1126/science.abk2820

This article has been republished from the following: materials† Note: Material may have been edited for length and content. For more information, please contact the said source.

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