Mouse study explores 3D structure of DNA in nerve cells

COLUMBUS, Ohio – New mouse model research led by scientists at The Ohio State University Wexner Medical Center, College of Medicine and Imperial College London explored how nerve cells repair themselves, which could lead to new treatments for nerve injuries.

Researchers studied how the 3D structure of DNA in nerve cells affects their ability to heal after injury.

“We found that certain DNA loops, called promoter-enhancer loops, are important for turning on genes that help nerves grow back. These loops are held together by a protein complex called cohesin. When this protein is missing, the DNA loops don't form correctly and the nerves can't heal properly,” said study first author and co-investigator Ilaria Palmisano, PhD, an assistant professor with Ohio State’s Department of Neuroscience and Department of Plastic and Reconstructive Surgery.

Palmisano carried out the work while at Imperial College London with co-investigator Professor Simone Di Giovanni, MD, PhD, at Imperial’s Department of Brain Sciences, and others, including scientists at the University of Miami.

Study findings are published online in the journal PNAS.

The ability of neurons (nerve’s cells) to regenerate in the peripheral nervous system partly depends on the activation of regenerative genes. This results in the synthesis of new proteins required for the repair of injured nerves.

“The chromatin, which is the ‘instruction manual’ of every cell, is tightly folded inside the cell nucleus. The way it unfolds or ‘opens’ when activated has an impact on how the instructions are ‘read’ and interpreted by the cells,” said study principal investigator Di Giovanni, who holds a Chair in Restorative Neuroscience at Imperial College.

Their past research in mice had shown that the activation of regenerative genes is affected by the organization of the chromatin. To induce the repair of injured nerves, the chromatin of the neurons must be opened, Palmisano said.

The team’s current research in mice has revealed another aspect of chromatin’s organization that is critical to the repair of injured nerves.

“We know that chromatin is organized into a complex structure, consisting of three-dimensional domains (genomic regions) within which the chromatin is folded into loops,” Palmisano said. “These loops enable contact between ‘genomic sites’ that lie far apart in the linear genomic sequence. These contact points are crucial because they allow communication between genes and their regulatory sequences, called ‘enhancers,’ resulting in boost of gene activity.”

Researchers found that after injury in the peripheral nervous system, specific contacts are formed between specific regenerative genes and specific enhancers in neurons.

“Our study has broad implications for neuronal biology and suggest new pathways for novel repair strategies,” Palmisano said. “Future directions will be to understand how the protein cohesin is activated after a nerve injury. In this way, we can further activate cohesin to promote regeneration in conditions where this is weak or absent, as in the central nervous system.”

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