Speaker: Dr.  Oliver Dreesen, Senior Principal Investigator, Cell Aging Laboratory,  A*STAR Skin Research Laboratories (A*SRL)

Talk Title:  Molecular functions of the nuclear lamina in cell aging & senescence

Abstract:

Hutchinson-Gilford Progeria (HGPS) is a premature aging syndrome caused by aberrant splicing of LMNA that results in a truncated and permanently farnesylated and membrane-tethered form of lamin A, called progerin. HGPS patients exhibit characteristics of premature aging, including early onset alopecia, skin thinning, altered pigmentation, lipodystrophy, bone defects, and die in their mid-teens due to cardiovascular complications. Our goal is to elucidate the molecular mechanism(s) that accelerate aging in progeria and understand its relevance to normal aging. To achieve this, we are using cell-based models (fibroblasts, iPSC) and doxycycline (DOX)-inducible expression systems. On a cellular level, progerin expression causes nuclear abnormalities, heterochromatin loss, DNA damage, nuclear lamina remodeling and premature senescence. Some of these defects can be prevented by ectopic expression of telomerase, or by modulating the DNA damage response specifically at telomeres. What remains unclear is how these different phenotypes are temporally and mechanistically linked, and whether they are a cause, or a consequence of cellular senescence. To address these questions, we introduced different lamin A mutants into primary and telomerase-immortalized human fibroblasts and used the DOX-inducible system to study how expression of these mutants perturbs cell function across the cell cycle. This system enabled us to delineate the precise temporal chain of events that occurs upon progerin expression and ultimately culminates in premature senescence. During these studies, we also identified and characterized nuclear lamina remodeling, including the degradation of lamin B1, as a hallmark to identify senescent cell types in vitro and in vivo. Collectively, these results provide evidence for a mechanistic link between the nuclear envelope, chromatin structure and telomeres, that is disrupted in progeria and possibly normal human aging.

Biography:

After completing his undergraduate degree in Bern, Switzerland, Oliver worked as a technician at the Pasteur Institute in Paris, the University of California, San Diego and Lonza AG in Switzerland. He received his Ph.D. from the Rockefeller University in New York City, where he studied the structure and function of telomeres and telomerase in Trypanosoma brucei. In 2009, he joined the Institute of Medical Biology in Singapore to study telomeres during cellular reprogramming and in rare genetic human diseases. Oliver was promoted to Project Leader in 2013, to Principal Investigator and Head of the Laboratory for Cell Aging in 2016, and to Senior Principal Investigator in 2022. He served as President of the Skin Research Society (Singapore) from 2019-2021 and is now leading the Skin Health & Aging cluster at the A*STAR Skin Research Labs (ASRL). His team is investigating the role of cellular senescence in human aging and disease.