How does your body produce millions of antibodies from one genome? New research reveals how two closely-related proteins help immune cells fold DNA, connecting distant genetic pieces to create diverse antibodies that help fend off disease.
In a new Nature Communications paper , a Michigan State University team discovered that the chromosome-organizing proteins STAG1 and STAG2 play distinct roles during antibody-gene assembly. STAG2 acts like a molecular gatekeeper, preventing DNA from forming oversized loops too soon, while STAG1 promotes long-range DNA interactions that are needed to assemble antibody genes.
Understanding how different antibodies are formed could eventually help scientists better understand why some immune cells develop abnormally, and how diseases like leukemia and lymphoma arise.
"The central question has been how cells bring together DNA segments that can be separated by millions of letters of genetic code with the precision required for antibody diversity," said Yu Zhang , assistant professor in the Department of Microbiology, Genetics, and Immunology and senior author of the study. "Our work shows that different forms of the same chromosome-organizing machinery help control this process in surprisingly different ways."
Human antibodies have identical DNA when they're first formed. That's a problem because the body is constantly bombarded by a wide variety of bacteria, viruses and pathogens.
To combat the onslaught, antibodies switch up their DNA by mixing and matching segments known as V, D and J. This is no small feat considering they don't sit next to one another along the long thread of DNA.
Enter cohesin. This protein acts like a drawstring on a hoodie, closing the long strand into a loop that fold in on one another in a process called loop extrusion.
Zhang's study discovered that two forms of cohesin, STAG1 and STAG2, play distinct roles at different stages of antibody-gene assembly. Without STAG2, STAG1 goes rogue, creating long loops of DNA and allowing gene segments to interact prematurely. And STAG1 works with another chromosome-organizing protein called CTCF, which controls chromosome structure and is required for STAG1 to efficiently create these long-range DNA interactions.
Later in antibody-gene assembly, both cohesin varieties work hand in hand, stitching the many V segments together across the long stretches of DNA. The result is a more diverse portfolio of antibodies.
"I think the crosstalk between computational and experimental analyses is becoming the driving force in understanding how complex genomes reorganize in the 3D space and the downstream functional impacts," said Jianrong Wang , associate professor at MSU who led the computational data integration and bioinformatics analysis for this study.
While this study focuses on antibody production, the proteins involved are used throughout the genome to keep DNA organized and functioning properly. Scientists have linked defects in these proteins to developmental disorders and several cancers. Zhang's findings could eventually help explain how those diseases develop.
"What makes this study exciting is that two highly similar versions of the same chromosome-organizing machinery can perform very different functions depending on the developmental context," said Zhang. "These mechanisms help ensure antibody genes are assembled in the correct order while still generating the enormous diversity needed for effective immune protection."
Funding was provided by the National Institutes of Health (Grants R01AI155775 and R35GM153479), the National Science Foundation (Grants DMS-2152011 and DBI-1942143) and a Strategic Partnership Grant from MSU.
By Stacy Kish and Bethany Mauger
