Changing gene expression at a distance: New insights into the genetic landscape of vascular cells’ response to shear stress
by Adrienne Mueller, PhD
October 13, 2022
Endothelial cells in blood vessel walls are sensitive to mechanical forces such as shear stress, which they routinely experience from blood flow. However, excessive shear stress can cause damage to the blood vessels leading to vascular obstruction in disease. How prone blood vessels are to damage from shear stress, as well as how well endothelial cells are able to repair the damage, is partly due to genetics. Endothelial cells have proteins that can sense the mechanical forces acting on the cells caused by the normal shear stress of physiologic flow called laminar shear stress. When laminar shear stress occurs, it triggers endothelial cells to express genes to help protect the vascular wall. KLF proteins, especially KLF4, have previously been identified as transcription factor proteins in endothelial cells that promote vascular protection in response to shear stress. Transcription factors are a class of proteins that act on the DNA within a cell to change the expression of other genes. Transcription factors often work locally at the genes of interest; influencing a cell’s transcription machinery to express more or less of the protein a gene encodes. However, sometimes transcription factors can act at a long distance, and change the expression of genes by influencing chromatin – huge structures that our DNA is packaged on to make chromosomes. Understanding the landscape of how KLF proteins influence gene expression – through local or distal enhancement of gene expression – would allow us to better understand the basis for vascular disease and our development of treatments.
In a recent study, a team of investigators led by Marlene Rabinovitch, MD, sought to map the enhancer landscape of vascular endothelial cells – specifically those of the pulmonary artery which carries blood from the heart to the lungs under physiologic laminar shear stress. The results of their study are published in a recent paper in Nature Communications, co-first-authored by Jan-Renier Moonen, MD, PhD and James Chappell, PhD.
Identifying distal, chromatin-organizing, enhancer sites is very challenging because these sites would be located in non-coding DNA regions. Only about 1% of our genome is comprised of coding regions, or genes, and the remaining 99% of our genome is non-coding DNA. This means that there is a lot of DNA to explore to try to find enhancer regions that KLF transcription factors act on. However, using a cadre of new bioinformatic and molecular techniques, the investigators showed that an increase in chromatin accessibility is associated with enhanced expression of vascular protective genes. They also were able to identify binding sites for KLF at both local and distal sites for vascular protective proteins. Further, the investigators demonstrated that KLF is necessary to mediate the chromatin changes at these enhancer sites. Specifically, it recruits a chromatin remodeling complex called SWI/SNF. Ultimately, the investigators determined that over 70% of genes whose expression is either enhanced or repressed in response to laminar shear stress are regulated by KLF4.
In summary, this study generated a blueprint of the genetic landscape that helps protect our vascular endothelial cells under conditions of normal shear stress. Genetic variants that affect this enhancer landscape under conditions of normal flow may make individuals at risk for vascular disease.
Additional Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Minyi Shi, Tsutomu Shinohara, Dan Li, Maxwell R. Mumbach, Fan Zhang, Ramesh V. Nair, Joseph Nasser, Daniel H. Mai, Shalina Taylor, Lingli Wang, Ross J. Metzger, Howard Y. Chang, Jesse M. Engreitz, and Michael P. Snyder.