Scientists engineer synthetic DNA to study 'architect' genes



Using innovative synthetic DNA technologies and genomic engineering in stem cells, researchers at New York University have manufactured artificial Hox genes, which regulate and dictate where cells go to develop tissues or organs.

Their research, which was published in Science, supports how Hox gene clusters assist cells in learning and remembering their location within the body.

An anterior-posterior axis, or a line that extends from the head to the tail, is a feature shared by almost all species, including people, birds, and fish. Hox genes serve as architects during development, laying out the blueprint for where cells will go along the axis and what body parts they will form. Hox genes control where organs and tissues grow, making the thorax or giving wings their proper anatomical placement.

Hox genes can malfunction due to dysregulation or mutation, leading to cell loss that can contribute to certain malignancies, birth abnormalities, and miscarriages.

According to co-senior author of the study Esteban Mazzoni, associate professor of biology at NYU, "I don't think we can understand development or disease without understanding Hox genes."

Despite being crucial for development, Hox genes are difficult to research. Only Hox genes are present in the region of DNA where they are found, and no other genes are present around them. They are tightly ordered into clusters (what scientists call a "gene desert"). Additionally, Hox clusters lack the repetitive sequences found in many other regions of the genome. These characteristics make them distinct, but they also make them challenging to examine using traditional gene editing without altering nearby Hox genes.                                      
a new beginning using synthetic DNA

Instead of using gene editing, could scientists analyze Hox genes better using fake Hox genes?                                                                                                    
"We are quite skilled at sequencing DNA or reading the genome. We can also modify the genome somewhat thanks to CRISPR. However, we still struggle when it comes to original writing "presented Mazzoni. Finding out what the smallest unit of the genome is required for a cell to know where it is in the body might be tested for sufficiency by writing or creating new sections of the genome.

Mazzoni collaborated with Jef Boeke, who is recognized for his work creating a synthetic yeast genome and who serves as the director of the Institute of System Genetics at the NYU Grossman School of Medicine. The goal of Boeke's lab was to apply this technology to mammalian cells.

By replicating DNA from the rat Hox genes, graduate student Sudarshan Pinglay created long strands of synthetic DNA in Boeke's lab. The DNA was then implanted precisely into mouse pluripotent stem cells by the researchers. The researchers were able to differentiate between the synthetic rat DNA and the natural cells of mice by using the various species.

"The eminent physicist Dr. Richard Feynman once said, "What I cannot build, I can not understand." We have come a long way in understanding Hox "Boeke, the study's co-senior author and professor of biochemistry and molecular pharmacology at NYU Grossman, stated.

The researchers could now investigate how Hox genes assist cells in learning and remembering their location thanks to the synthetic Hox DNA present in mouse stem cells. In mammals, regulatory areas that manage the activation of the Hox genes surround Hox clusters. It remained unclear if the cluster was necessary for the cells to learn and remember their location on its own or in combination with other components.

The researchers found that these gene-dense clusters alone hold all of the data required for cells to decode and remember a positional signal. This supports a long-held theory about Hox genes that was previously challenging to test, according to which the compact shape of Hox clusters is what aids cells in learning their location.

Future studies on animal development and human disorders will be possible thanks to the development of synthetic DNA and artificial Hox genes.

"Different species have various shapes and architectures, which are mostly influenced by how Hox clusters are expressed. For example, a snake has a lengthy thorax and no limbs, whereas a skate only has limbs. A deeper comprehension of Hox clusters might facilitate our comprehension of how these systems are transformed and adapted to produce various species "Mazzoni stated.

More generally, this synthetic DNA technology—for which we have created a sort of factory—will be helpful for researching diseases with complex genomics since it will allow for the creation of models that are much more precise, according to Boeke                                                                                                                                                                                                                                New York University

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