Investigating Rapid Nuclear Mechanotransduction by Mapping Genome-wide Changes in Transcription

Jan Lammerding - Investigating Rapid Nuclear Mechanotransduction by Mapping Genome-wide Changes in Transcription and Chromatin Accessibility

Mounting evidence suggests that the nucleus plays a crucial part in cellular mechanotransduction to initiate cellular functions like differentiation or stress response. It is not yet known, however, if changes in chromosomal organization and the concurrent gene activation following mechanical stimuli are a direct consequence of nuclear deformation, or if they are due to the action of upstream cytoplasmic mechanotransduction pathways. To address this knowledge gap, we interrogated the immediate response of the transcriptome (PRO-seq) and genome organization (ATAC-seq) following cyclical stretch application over very short time-points (2-30 minutes). PRO-seq, with increased sensitivity over traditional RNA-seq, identified the activation of novel and known mechanoresponsive genes, encoding for transcription factors, as early as 2 minutes after mechanical stretch, a much shorter timeframe than previously reported. PRO-seq mapping of polymerase (Pol II) processing along the gene body suggests that gene activation was initiated within 1 min of the stretch stimulus, faster than cytoplasmic signaling cascades, which take several minutes to reach the nucleus. Furthermore, the observation of accumulated paused Pol II within the promoter-proximal region of some of the identified genes prior to mechanical stimulus suggests different modalities of activation within the stretch-activated genes. Cross-referencing PRO-seq with ATAC-seq revealed that promoter regions of mechanically-induced genes were already accessible prior to mechanical stretching, and genome-wide chromatin accessibility did not increase further with mechanical stretch. These results point to a previously unrecognized role of the nucleus itself regulating mechanoresponsive genes, primed for rapid activation through polymerase pause release and elongation.

About Jan Lammerding
Jan Lammerding is a professor in the Meinig School of Biomedical Engineering and the Weill Institute for Cell and Molecular Biology at Cornell University. He received a Bachelor of Engineering degree from the Thayer School of Engineering at Dartmouth College, earned a Diploma Ingenieur degree in Mechanical Engineering from the University of Technology in Aachen, Germany, and completed his Ph.D. in Biological Engineering at the Massachusetts Institute of Technology. Following a brief postdoctoral fellowship, he started his faculty career at Harvard Medical School/Brigham and Women’s Hospital before being recruited to Cornell University in 2011. At Cornell University, Dr. Lammerding continues to conduct pioneering research on ‘nuclear mechanobiology, investigating how the mechanical properties of the cell nucleus modulate cellular functions, and how physical forces acting on the nucleus affect its structure and processes, with important applications in muscular dystrophy, heart disease, and cancer. Dr. Lammerding has published over 100 peer-reviewed articles, including in Nature, Science, and PNAS. His research is supported by grants from the National Institutes of Health, the National Science Foundation, the Leducq Foundation, and the Volkswagen Foundation. Dr. Lammerding’s work has received several prestigious awards, including a National Science Foundation CAREER Award and the Keith Porter Award of the American Society for Cell Biology (ASCB). Dr. Lammerding is a Fellow of the Biomedical Engineering Society (BMES), the American Institute for Medical and Biological Engineering (AIMBE), and the ASCB. At Cornell University, Dr. Lammerding previously served as Director of Graduate Studies at the Meinig School, and he has been recognized with several awards for research, teaching, and mentoring, including from the College of Engineering and the Professional Student Assembly. More information on the research in the Lammerding lab is available at: http://lammerding.wicmb.cornell.edu/.

Sponsored by the Center for Physical Genomics and Engineering, the Cancer and Physical Sciences Program at the Robert H. Lurie Comprehensive Cancer Center, and NIH Grants T32GM142604 and U54CA268084