CSB Emeritus Faculty
Olivia Pereira-Smith, Ph.D.Professor Emeritus
Worcester Polytechnic Institute, 1981
Department of Cellular and Structural Biology
The Sam and Ann Barshop Institute for Longevity and Aging Studies Ph.D.
Worcester Polytechnic Institute Postdoctoral
W. Alton Jones Cell Science Center
The limited division of normal cells in culture is proposed as a model for cell aging. To understand the molecular and genetic basis for this loss of cell division in normal cells, we have chosen to study abnormal human cells (tumor derived, virus transformed) that have escaped from senescence and proliferate indefinitely (immortal). We have found that hybrids from fusion of various immortal cells with normal cells regain the senescent phenotype. This indicates that the phenotype of immortality is the result of recessive changes in genes regulating growth. We then fused various immortal human cells with each other. If the cell lines had immortalized through the same changes, immortal hybrids would be obtained. If different events had led to immortalization, hybrids would have limited division since the recessive (defective) genes of each cell line would be complemented by the good genes present in the other.
By this analysis we have identified four complementation groups for indefinite division. Using microcell fusion we determined that a normal human chromosome 4 can suppress the immortal phenotype in immortal cells lines assigned to group B. We then cloned the gene MORF4 as the cause of this effect. It is a member of a family of genes that are involved in chromatin remodeling and transcriptional regulation.
The MORF related genes, MRG15 and MRGX encode proteins that are present in multiple nucleoprotein complexes and the composition of other proteins in these complexes determines whether a gene promoter is activated or repressed. MRG15 has now been implicated in chromatin remodeling. It is involved in transcriptional regulation essential for cell proliferation, DNA repair, regulation of translation from RNA to protein and also RNA splicing via histone code recognition. Studies with neural stem/progenitor cells derived from brains of MRG15 null and wild type embryos and the initial published results indicate that null cells have defects in both proliferation and differentiation into neurons but not glial cells.
We are also involved in collaborative studies on telomeres and telomerase with Drs. I Rubelj, V Gorbunova and A Seluanov, and on mortalin with Drs R Wadhwa and S Kaul.
Cell culture of normal and immortal human and mouse cells, use of genetically modified mice, immunostaining and histochemistry, molecular and biochemical techniques: Southern, northern, western, immunoprecipitation, chromatin immunoprecipitation, PCR, real time PCR, plasmid constructs, adenoviral constructs.
Tominaga K, Pereira-Smith OM. (2012) The role of chromatin reorganization in the process of cellular senescence. Curr Drug Targets. 2012 Sep 17.
Chen M, Pereira-Smith OM, Tominaga K. (2011) Loss of the chromatin regulator MRG15 limits neural stem/progenitor cell proliferation via increased expression of the p21 Cdk inhibitor. Stem Cell Res. 2011 Jul;7(1):75-88.
Martrat G, Maxwell CM, Tominaga E, et al. (2011) Exploring the link between MORF4L1 and risk of breast cancer. Breast Cancer Res. 2011 Apr 5;13(2):R40.
Zhang H, Li Y, Yang J, Tominaga K, Pereira-Smith OM, Tower J. (2010) Conditional inactivation of MRG15 gene function limits survival during larval and adult stages of Drosophila melanogaster. Exp Gerontol. 2010 Jun 23.
Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. (2010) Regulation of alternative splicing by histone modifications. Science. 2010 Feb 19;327(5968):996-1000.
Tominaga K, Tominaga E, Ausserlechner MJ, Pereira-Smith OM. (2010) The cell senescence inducing gene product MORF4 is regulated by degradation via the ubiquitin/proteasome pathway. Exp Cell Res. 2010 Jan 1;316(1):92-102.
Chen M, Takano-Maruyama M, Pereira-Smith OM, Gaufo GO, Tominaga K. (2009) MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cells. J Neurosci Res. 2009 May 15;87(7):1522-31.