Michelle Longworth, PhD
Associate Staff
Email: longwom@ccf.org
Location:
Cleveland Clinic Main Campus
Research
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 and maintenance of tissues and uncover novel pathways that could be exploited to prevent disease progression.
Biography
Dr. Longworth received her PhD from Northwestern University, where she studied Human Papillomavirus oncogenes and their interactions with chromatin regulators and tumor suppressor proteins in the laboratory of Dr. Laimonis Laimins. She then did her postdoctoral fellowship at the Mass General Hospital Cancer Center in the laboratory of Dr. Nicholas Dyson where she studied the regulation of chromatin organization and gene expression by retinoblastoma proteins and condensins. Dr. Longworth started her lab at the Lerner Research Institute in December of 2010. In addition to running the lab, Dr. Longworth is the Director of Staff Engagement in the LRI Faculty Center. In this role, Dr. Longworth works with the other members of the Faculty Center to develop and implement ideas to promote interactions, communication and collaboration among LRI staff members. Dr. Longworth is also the Director of the RISE in Cleveland program. This program provides local high school students with paid internships that allow them to gain experience and perform cutting edge research in the laboratories of the LRI during the summer.
Education & Professional Highlights
Education & Fellowships
Postdoctoral Fellowship- Massachusetts General Hospital Cancer Center (2005-2010)
Molecular Oncology
Charlestown, MA
Graduate School- Northwestern University Feinberg School of Medicine (2000-2005)
Integrated Graduate Program in the Biological Sciences, Cancer Biology Track
Chicago, IL
Undergraduate- Miami University of Ohio (1996-2000)
BA in Microbiology
Oxford, OH
Research
Interplay between genome organizers and retrotransposable elements
Our lab discovered that condensin proteins repress retrotransposon expression and activity in both primary and transformed human cell lines (Ward et. al. PLOS Genetics, 2017) (Ward et. al. Nucleic Acids Research, 2022), as well as in vivo, in Drosophila melanogaster (Schuster et. al. PLOS Genetics, 2013). Current projects in the lab are now focused on understanding the signaling pathways that condensins (and other genome organizers) communicate with to facilitate repression, as well as the identification of novel mechanisms used by condensins and other genome organizing complexes to prevent retrotransposition.
Antimicrobial roles for condensins
We discovered that condensin proteins are dysregulated in colonic epithelial cells of patients with a type of Inflammatory Bowel Disease (IBD) called ulcerative colitis. This led to the discovery that condensins possess antimicrobial functions in intestinal epithelial cells (Schuster et. al. Gastroenterology, 2015). Currently, we are investigating whether dysregulation of condensin proteins also occurs in patients with a second type of IBD, Crohn’s Disease and whether this may contribute to disease pathogenesis.
Condensin-mediated regulation of neurodevelopment
Condensin protein mutations have been identified in microcephaly patients, however the mechanisms by which loss of condensin function leads to microcephaly are not well understood. We are using Drosophila melanogaster as a model organism to uncover new roles for condensin proteins in neurodevelopment, with the ultimate goal of identifying new molecular pathways involved in the development of microcephaly (Manuscript in revision, 2023). Conservation of these pathways will be then studied in mice and human cerebral organoids.
Our Team
Selected Publications
Ward JR, Khan A, Torres S, Crawford B, Nock S, Frisbie T, Moran JV, Longworth MS. Condensin I and condensin II proteins form a LINE-1 dependent super condensin complex and cooperate to repress LINE-1. Nucleic Acids Res. 2022 Oct 14;50(18):10680-10694. doi: 10.1093/nar/gkac802. PubMed PMID: 36169232; PubMed Central PMCID: PMC9561375.
Lechuga S, Cartagena-Rivera AX, Khan A, Crawford BI, Narayanan V, Conway DE, Lehtimäki J, Lappalainen P, Rieder F, Longworth MS, Ivanov AI. A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair. FASEB J. 2022 May;36(5):e22290. doi: 10.1096/fj.202200154R. PubMed PMID: 35344227; PubMed Central PMCID: PMC9044500.
Welch N, Singh SS, Kumar A, Dhruba SR, Mishra S, Sekar J, Bellar A, Attaway AH, Chelluboyina A, Willard BB, Li L, Huo Z, Karnik SS, Esser K, Longworth MS, Shah YM, Davuluri G, Pal R, Dasarathy S. Integrated multiomics analysis identifies molecular landscape perturbations during hyperammonemia in skeletal muscle and myotubes. J Biol Chem. 2021 Sep;297(3):101023. doi: 10.1016/j.jbc.2021.101023. Epub 2021 Jul 31. PubMed PMID: 34343564; PubMed Central PMCID: PMC8424232.
Yin S, Ray G, Kerschner JL, Hao S, Perez A, Drumm ML, Browne JA, Leir SH, Longworth M, Harris A. Functional genomics analysis of human colon organoids identifies key transcription factors. Physiol Genomics. 2020 Jun 1;52(6):234-244. doi: 10.1152/physiolgenomics.00113.2019. Epub 2020 May 11. PubMed PMID: 32390556; PubMed Central PMCID: PMC7311676.
Farabaugh KT, Krokowski D, Guan BJ, Gao Z, Gao XH, Wu J, Jobava R, Ray G, de Jesus TJ, Bianchi MG, Chukwurah E, Bussolati O, Kilberg M, Buchner DA, Sen GC, Cotton C, McDonald C, Longworth M, Ramakrishnan P, Hatzoglou M. PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation. Elife. 2020 Mar 16;9. doi: 10.7554/eLife.52241. PubMed PMID: 32175843; PubMed Central PMCID: PMC7145421.
Deutschman E, Ward JR, Kumar A, Ray G, Welch N, Lemieux ME, Dasarathy S, Longworth MS. Condensin II protein dysfunction impacts mitochondrial respiration and mitochondrial oxidative stress responses. J Cell Sci. 2019 Nov 20;132(22). doi: 10.1242/jcs.233783. PubMed PMID: 31653782; PubMed Central PMCID: PMC6899004.
Ray G, Longworth MS. Epigenetics, DNA Organization, and Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019 Jan 10;25(2):235-247. doi: 10.1093/ibd/izy330. Review. PubMed PMID: 30407525; PubMed Central PMCID: PMC6327229.
Deutschman E, Ward JR, Ho-A-Lim KT, Alban TJ, Zhang D, Willard B, Lemieux ME, Lathia JD, Longworth MS. Comparing and Contrasting the Effects of Drosophila Condensin II Subunit dCAP-D3 Overexpression and Depletion in Vivo . Genetics. 2018 Oct;210(2):531-546. doi: 10.1534/genetics.118.301344. Epub 2018 Aug 1. PubMed PMID: 30068527; PubMed Central PMCID: PMC6216582.
Kim Y, West GA, Ray G, Kessler SP, Petrey AC, Fiocchi C, McDonald C, Longworth MS, Nagy LE, de la Motte CA. Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Matrix Biol. 2018 Mar;66:93-109. doi: 10.1016/j.matbio.2017.09.003. Epub 2017 Oct 1. PubMed PMID: 28978412; PubMed Central PMCID: PMC5845474.
Deutschman E, Longworth MS. New insights into the pRB/ Condensin II interaction. Cell Cycle. 2017 Oct 18;16(20):1859-1860. doi: 10.1080/15384101.2017.1360658. Epub 2017 Aug 18. PubMed PMID: 28820335; PubMed Central PMCID: PMC5638378.
Ward JR, Vasu K, Deutschman E, Halawani D, Larson PA, Zhang D, Willard B, Fox PL, Moran JV, Longworth MS. Condensin II and GAIT complexes cooperate to restrict LINE-1 retrotransposition in epithelial cells. PLoS Genet. 2017 Oct;13(10):e1007051. doi: 10.1371/journal.pgen.1007051. eCollection 2017 Oct. PubMed PMID: 29028794; PubMed Central PMCID: PMC5656329.
Alvarado AG, Thiagarajan PS, Mulkearns-Hubert EE, Silver DJ, Hale JS, Alban TJ, Turaga SM, Jarrar A, Reizes O, Longworth MS, Vogelbaum MA, Lathia JD. Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression. Cell Stem Cell. 2017 Apr 6;20(4):450-461.e4. doi: 10.1016/j.stem.2016.12.001. Epub 2017 Jan 12. PubMed PMID: 28089910; PubMed Central PMCID: PMC5822422.
Farabaugh KT, Majumder M, Guan BJ, Jobava R, Wu J, Krokowski D, Gao XH, Schuster A, Longworth M, Chan ED, Bianchi M, Dey M, Koromilas AE, Ramakrishnan P, Hatzoglou M. Protein Kinase R Mediates the Inflammatory Response Induced by Hyperosmotic Stress. Mol Cell Biol. 2017 Feb 15;37(4). doi: 10.1128/MCB.00521-16. Print 2017 Feb 15. PubMed PMID: 27920257; PubMed Central PMCID: PMC5288580.
Klebanow LR, Peshel EC, Schuster AT, De K, Sarvepalli K, Lemieux ME, Lenoir JJ, Moore AW, McDonald JA, Longworth MS. Drosophila Condensin II subunit Chromosome-associated protein D3 regulates cell fate determination through non-cell-autonomous signaling. Development. 2016 Aug 1;143(15):2791-802. doi: 10.1242/dev.133686. Epub 2016 Jun 17. PubMed PMID: 27317808; PubMed Central PMCID: PMC5004906.
Kemp JR, Longworth MS. Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer. Front Chem. 2015;3:68. doi: 10.3389/fchem.2015.00068. eCollection 2015. Review. PubMed PMID: 26734601; PubMed Central PMCID: PMC4679865.
Schuster AT, Homer CR, Kemp JR, Nickerson KP, Deutschman E, Kim Y, West G, Sadler T, Stylianou E, Krokowski D, Hatzoglou M, de la Motte C, Rubin BP, Fiocchi C, McDonald C, Longworth MS. Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. Gastroenterology. 2015 Jun;148(7):1405-1416.e3. doi: 10.1053/j.gastro.2015.02.013. Epub 2015 Feb 18. PubMed PMID: 25701737; PubMed Central PMCID: PMC4446190.
Schuster AT, Sarvepalli K, Murphy EA, Longworth MS. Condensin II subunit dCAP-D3 restricts retrotransposon mobilization in Drosophila somatic cells. PLoS Genet. 2013 Oct;9(10):e1003879. doi: 10.1371/journal.pgen.1003879. Epub 2013 Oct 31. PubMed PMID: 24204294; PubMed Central PMCID: PMC3814330.
Aranjuez G, Kudlaty E, Longworth MS, McDonald JA. On the role of PDZ domain-encoding genes in Drosophila border cell migration. G3 (Bethesda). 2012 Nov;2(11):1379-91. doi: 10.1534/g3.112.004093. Epub 2012 Nov 1. PubMed PMID: 23173089; PubMed Central PMCID: PMC3484668.
Herr A, Longworth M, Ji JY, Korenjak M, Macalpine DM, Dyson NJ. Identification of E2F target genes that are rate limiting for dE2F1-dependent cell proliferation. Dev Dyn. 2012 Nov;241(11):1695-707. doi: 10.1002/dvdy.23857. Epub 2012 Sep 17. PubMed PMID: 22972499; PubMed Central PMCID: PMC3760379.
Longworth MS, Walker JA, Anderssen E, Moon NS, Gladden A, Heck MM, Ramaswamy S, Dyson NJ. A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity. PLoS Genet. 2012;8(4):e1002618. doi: 10.1371/journal.pgen.1002618. Epub 2012 Apr 5. PubMed PMID: 22496667; PubMed Central PMCID: PMC3320600.
Black JC, Allen A, Van Rechem C, Forbes E, Longworth M, Tschöp K, Rinehart C, Quiton J, Walsh R, Smallwood A, Dyson NJ, Whetstine JR. Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. Mol Cell. 2010 Dec 10;40(5):736-48. doi: 10.1016/j.molcel.2010.11.008. PubMed PMID: 21145482.
Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 2010 Jul 1;24(13):1364-76. doi: 10.1101/gad.1917310. Epub 2010 Jun 15. PubMed PMID: 20551165; PubMed Central PMCID: PMC2895196.
Longworth MS, Dyson NJ. pRb, a local chromatin organizer with global possibilities. Chromosoma. 2010 Feb;119(1):1-11. doi: 10.1007/s00412-009-0238-0. Epub 2009 Aug 28. Review. PubMed PMID: 19714354; PubMed Central PMCID: PMC3760338.
Longworth MS, Herr A, Ji JY, Dyson NJ. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev. 2008 Apr 15;22(8):1011-24. doi: 10.1101/gad.1631508. Epub 2008 Mar 26. PubMed PMID: 18367646; PubMed Central PMCID: PMC2335323.
Careers
6/2023: We are hiring a senior technician. The candidate will participate in daily research projects (collaborative and individual projects), act as lab manager, assist in writing scientific papers, present research at national and international conferences, and help to train lab personnel.
6/2023: We want graduate students! Email Dr. Longworth if you are interested in doing a lab rotation and are a student at one of the following places: CCLCM/Molecular Medicine program, Case Western BSTP or MSTP programs, Cleveland State University, Kent State University, Akron University.
Research News
With this funding, Drs. O’Connor and Longworth will investigate how host cells attempt to subvert human cytomegalovirus replication.