Department of Cellular and Molecular Medicine
Michelle S. Longworth, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-8082
Fax: (216) 445-0512
We investigate how changes to DNA organization within the nucleus of a cell impact development and disease. The efficient compaction of DNA during cellular division ensures equal distribution of DNA into daughter cells and prevents aneuploidy, which has been implicated as a major driver of tumor development. DNA organization is also important for the control of transcriptional programs following exposure to biological stresses including inflammation and bacterial infection.
A number of complexes exist to efficiently organize DNA. Condensin II is one such complex that promotes condensation of DNA in prophase of mitosis and organizes DNA loops and formation of chromosome territories during interphase. Our lab investigates the mechanisms by which this complex and similar groups of proteins organize DNA and regulate transcription in human cells and tissues, as well as in the model organism of Drosophila melanogaster.
Current lab projects include:
Elucidating the role of Condensin II in regulating cell fate decisions in Drosophila
Investigating the mechanisms by which Condensin II prevents retrotransposition
Characterizing the role of the Condensin II subunit, CAP-D3 in innate immune signaling and the response to enteric infection
Exploring a potential role for CAP-D3/Condensin II in the pathogenesis of Inflammatory Bowel Disease
In other words ...
The disorganization of the genetic material (DNA) within cells can have dire consequences for the health of an organism, ultimately resulting in death or disease. We study the proteins that help to maintain DNA organization, and the ways by which they accomplish these important functions. By studying these processes, we hope to gain a better understanding of how cells respond to various stresses to ensure the normal development of tissues and uncover novel pathways that could be exploited to prevent disease progression.
Klebanow, L.R., Peshel, E.C., Schuster, A.T., De, K., Sarvepalli, K., Lemieux, M.E., Lenoir, J.J., Moore, A.W., McDonald, J.A., and Longworth, M.S. (2016) Drosophila Condensin II subunit, Chromosome Associated Protein-D3, regulates cell fate determination through non-cell autonomous signaling. Development (in press).
Kemp, J.R. and Longworth, M.S. (2015) Crossing the LINE toward genomic instability: LINE-1 retrotransposition in cancer. Frontiers in Chemistry. Dec 16;3:68. doi: 10.3389/fchem.2015.00068. eCollection
Andrew T. Schuster*, Craig R. Homer*, Jacqueline R. Kemp, Kourtney P. Nickerson, Emily Deutschman, YeoJung Kim, Gail West, Tammy Sadler, Eleni Stylianou, Dawid Krokowski, Maria Hatzoglou, Carol de la Motte, Brian P. Rubin, Claudio Fiocchi, Christine McDonald^, and Michelle S. Longworth^. (2015) CAP-D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. *co-first authors ^co-corresponding authors. Gastroenterology. 2015 Jun;148(7):1405-16.e3. doi: 10.1053/j.gastro.2015.02.013. Epub 2015 Feb 18.
Schuster AT, Sarvepalli K, Murphy EA, and Longworth M.S. (2013) Condensin II subunit dCAP-D3 restricts retrotransposon mobilization in Drosophila somatic cells. PLOS Genetics. Oct;9(10):e1003879. doi: 10.1371/journal.pgen.1003879.
Longworth, M.S*., Walker, J.A., Anderssen, E., Moon, N.S., Gladden, A., Heck, M.M.S., Ramaswamy, S. and Dyson, N.J. (2012). A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity. PLOS Genetics. 8: e1002618. *Corresponding author.
Manning, A., Longworth, M.S., and Dyson, N.J. (2010). Loss of pRB causes defects in Sister Chromatid Cohesion and Chromosomal Instability. Genes and Development. 24:1364-1376. Associated Papers/Comments: 1) Sage J. and Straight. A.F. (2010) RB’s Original CIN? Genes and Development. 24: 1329-1333. 2) Faculty of 1000 Biology.
Longworth, M.S. and Dyson, N.J. (2010) pRB, a local chromatin organizer with global
possibilities. Chromosoma. Feb 119 (1) 1-11.
Longworth, M.S., Herr, A., Ji, J.Y., and Dyson, N.J. (2008) RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein, dCAP-D3. Genes and Development. 22:1011-1024. Associated Papers/ Comments: 1) Lavoie B.D. pRb and condensin--local control of global chromosome structure. Genes and Development. 2008; 22: 964-969. 2) Faculty of 1000 Biology.