Chromatin displays different dynamics in cells during organ-formation

Recent research from the School of Medicine has illuminated the development of the liver, lungs, and digestive system. This result may have significant ramifications for the comprehension of cancer.

Mammals evolve from what is referred to as a “primitive gut tube,” which gives rise to the stomach, colon, intestines, pancreas, liver, lungs, esophagus, pharynx (throat), and thyroid. However, it is unclear to scientists exactly what causes the same cells in the gut tube to “differentiate” into different organs. How precisely does a cell in the gastrointestinal tube recognize that it belongs in the lung and not the stomach?

Insights have been discovered by Chongzhi Zang, PhD, of UVA, and colleagues, showing how genetic material called chromatin interacts with other components to switch genes on and off in order to complete this crucial change.

Gut development is a fascinating dynamic process, from which we can learn how the same genome can create many different types of cells in different organs. We knew the genes being used in different organs would start to show some differences in the early stages of development, but this was the first time that we found how such differences were controlled by chromatin during the organ-formation process.”

Chongzhi Zang, Center for Public Health Genomics and Cancer Center, University of Virginia

Understanding organ development

Zang and his colleagues used state-of-the-art genomics technology known as “single-cell ATAC-seq” to create a detailed “map” of the chromatin pattern changes that occur inside individual cells in the gut tube during organ formation in mice.

The team included collaborators led by Tae-Hee Kim, PhD, of the University of Toronto in Canada. By doing this, they have filled in a number of significant gaps in the knowledge of how mammals acquire their organs.

The scientists discovered that chromatin exhibits distinct dynamics in cells that develop into the liver and lungs, respectively. In a sophisticated arrangement, chromatin interacts with “transcription factors” to prepare the cells for the significant roles they are destined to play.

Later in the process of development, these interactions will further hone the organs that are forming, allowing the intestine, for instance, to split into the big and small intestines.

This intricate process must go exactly as planned. The scientists discovered that mistakes can have disastrous effects, such as interfering with a lab mouse’s ability to produce a healthy pancreas and gut. The pancreas underwent significant alterations, including the development of numerous large, cyst-like formations.

Precancerous lesions are caused by “cell fate” abnormalities that happen in the early stages of pancreatic cancer, according to researchers. Understanding how organs develop and what may go wrong could therefore provide crucial information on how some malignant tumors form.

A better understanding of how genes work in the genome during organ development can give us insights into the mechanisms underlying initiation of many types of cancer. We use state-of-the-art technologies to tackle these complex problems and believe that these fundamental discoveries, one step at a time, will eventually inspire new therapeutic development and benefit cancer patients in the future.”

Chongzhi Zang, Center for Public Health Genomics and Cancer Center, University of Virginia