Building artificial Hox genes allows researchers to see how cells learn their location in the body

New York University researchers have created 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 the clusters of Hox genes help cells learn and remember where they are in the body.

Hox genes as architects of the body

Almost 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, determining the plane from which cells go along the axis, as well as the parts of the body they compose. Hox genes ensure that organs and tissues grow in the right place, forming the thorax or placing the wings in the correct anatomical positions.

Whether Hox genes fail due to misregulation or mutation, cells can be lost, playing a role in certain cancers, birth defects and miscarriages.

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

Despite their importance in development, Hox genes are difficult to study. They are tightly organized in clusters, with only Hox genes in the piece of DNA where they are and no other genes around them (what scientists call a “gene desert”). And while many parts of the genome have repeating elements, Hox clusters have no such repeats. These factors make them unique but difficult to study with conventional gene editing without affecting neighbors. Hox Genoa.

Start over with synthetic DNA

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

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

Mazzoni teamed up with Jef Boeke, director of the Institute of System Genetics at NYU Grossman School of Medicine, known for his work synthesizing a synthetic yeast genome. Boeke’s lab was looking to translate this technology to mammalian cells.

Graduate student Sudarshan Pinglay of Boeke’s lab made long strands of synthetic DNA by copying DNA from the Hox rat genes. The researchers then delivered the DNA to a specific location in mouse pluripotent stem cells. Using the different species allowed the researchers to distinguish between synthetic rat DNA and natural mouse cells.

“Dr. Richard Feynman said, ‘What I can’t create, I don’t understand.’ We are now one giant step closer to understanding Hoxsaid Boeke, who is also a professor of biochemistry and molecular pharmacology at NYU Grossman and co-lead author of the study.

Studying Hox groups

With the artificial Hox DNA in mouse stem cells, researchers could now explore how Hox genes help cells learn and remember where they are. In mammals, Hox clusters are surrounded by regulatory regions that control Hox genes are activated. It was unclear whether the cluster alone or the cluster plus other elements was necessary for cells to learn and remember where they are.

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

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

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

“More broadly, this synthetic DNA technology, for which we have built a kind of factory, will be useful for studying genomically complicated diseases and we now have a method to produce much more precise models for them,” Boeke said. .

This work was supported in part by the National Institutes of Health (grants RM1HG009491, R01AG075272, R01NS100897, R01GM127538, and F32CA239394), New York State Stem Cell Science (C322560GG), and Melanoma Research Foundation (687306).

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