Location: Cleveland Clinic Main Campus
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.
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), 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 to prevent retrotransposition.
Antimicrobial roles for condensins We discovered that condensin II proteins promote the clearance of potentially pathogenic bacteria in Drosophila melanogaster (Longworth et. al. PLOS Genetics, 2012) and in human intestinal epithelial cells (Schuster et al. Gastroenterology 2015). We are now studying the mechanisms by which condensin proteins regulate transcription of various genes important for bacterial clearance, and, in a collaboration with the McDonald lab at the Lerner Research Institute, we are identifying the anti-microbial signaling pathways that condensins interact with. Additionally, we are examining the importance of condensin-mediated innate immune signaling in the maintenance of the intestinal epithelial barrier. We determined that intestinal epithelial cells exhibit dysregulated NCAPD3 expression, and we are now exploring the consequences of this dysregulation for intestinal epithelial homeostasis.
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. Conservation of these pathways will be then studied in mice and human cerebral organoids.
Condensin II protein dysfunction impacts mitochondrial repiration and mitochondrial oxidative stress responses. Deutschman E, Ward JR, Kumar A, Ray G, Welch N, Lemieux ME, Dasarathy S, Longworth MS. J Cell Sci. 2019 Nov 20;132(22). pii: jcs233783. doi: 10.1242/jcs.233783. PMID: 31653782
Epigenetics, DNA Organization, and Inflammatory Bowel Disease.
Ray G, Longworth MS.
Inflamm Bowel Dis. 2019 Jan 10;25(2):235-247. doi: 10.1093/ibd/izy330.PMID: 30407525
Comparing and Contrasting the Effects of Drosophila Condensin II Subunit dCAP-D3 Overexpression and Depletion in Vivo. Deutschman E, Ward JR, Ho-A-Lim KT, Alban TJ, Zhang D, Willard B, Lemieux ME, Lathia JD, Longworth MS. Genetics. 2018 Aug 1. pii: genetics.301344.2018. doi: 10.1534/genetics.118.301344. [Epub ahead of print]PMID 30068527
Condensin II and GAIT complexes cooperate to restrict LINE-1 retrotransposition in epithelial cells.
Ward JR, Vasu K, Deutschman E, Halawani D, Larson PA, Zhang D, Willard B, Fox PL, Moran JV, Longworth MS.
PLoS Genet. 2017 Oct 13;13(10):e1007051. doi: 10.1371/journal.pgen.1007051. eCollection 2017 Oct.PMID 29028794
Condensin II and GAIT Complexes Cooperate to Restrict LINE-1 Retrotransposition in Epithelial Cells. Jacqueline R. Ward, Kommireddy Vasu, Emily Deutschman, Dalia Halawani, Peter A. Larson, Dongmei Zhang, Belinda Willard, Paul L. Fox, John V. Moran, Michelle S. Longworth. PLOS Genetics. 2017; Accepted and in press.
Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Kim Y, West GA, Ray G, Kessler SP, Petrey AC, Fiocchi C, McDonald C, Longworth MS, Nagy LE, de la Motte CA. Matrix biology : journal of the International Society for Matrix Biology. 2017; PubMed [journal]PMID: 28978412.
New insights into the pRB/ Condensin II interaction. Deutschman E, Longworth MS. Cell cycle. 2017; :1-2. PubMed [journal]PMID: 28820335.
Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression. 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. Cell stem cell. 2017; 20(4):450-461.e4. PubMed [journal]PMID: 28089910.
Protein Kinase R Mediates the Inflammatory Response Induced by Hyperosmotic Stress. 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. Molecular and cellular biology. 2017; 37(4).PubMed [journal]PMID: 27920257 PMCID: PMC5288580.
Drosophila Condensin II subunit Chromosome-associated protein D3 regulates cell fate determination through non-cell-autonomous signaling. Klebanow LR, Peshel EC, Schuster AT, De K, Sarvepalli K, Lemieux ME, Lenoir JJ, Moore AW, McDonald JA, Longworth MS. Development (Cambridge, England). 2016; 143(15):2791-802. PubMed [journal]PMID: 27317808 PMCID: PMC5004906.
Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. 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. Gastroenterology. 2015; 148(7):1405-1416.e3. NIHMSID: NIHMS665545. PubMed [journal]PMID: 25701737 PMCID: PMC4446190
Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer. Kemp JR, Longworth MS. Frontiers in chemistry. 2015; 3:68. PubMed [journal]PMID: 26734601 PMCID: PMC4679865.
Condensin II subunit dCAP-D3 restricts retrotransposon mobilization in Drosophila somatic cells. Schuster AT, Sarvepalli K, Murphy EA, Longworth MS. PLoS genetics. 2013; 9(10):e1003879. PubMed [journal]PMID: 24204294 PMCID: PMC3814330.
On the role of PDZ domain-encoding genes in Drosophila border cell migration. Aranjuez G, Kudlaty E, Longworth MS, McDonald JA. G3 (Bethesda, Md.). 2012; 2(11):1379-91. PubMed [journal]PMID: 23173089 PMCID: PMC3484668.
Identification of E2F target genes that are rate limiting for dE2F1-dependent cell proliferation. Herr A, Longworth M, Ji JY, Korenjak M, Macalpine DM, Dyson NJ. Developmental dynamics : an official publication of the American Association of Anatomists. 2012; 241(11):1695-707. NIHMSID: NIHMS504348. PubMed [journal]PMID: 22972499 PMCID: PMC3760379.
A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity. Longworth MS, Walker JA, Anderssen E, Moon NS, Gladden A, Heck MM, Ramaswamy S, Dyson NJ. PLoS genetics. 2012; 8(4):e1002618. PubMed [journal]PMID: 22496667 PMCID: PMC3320600.
Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. 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. Molecular cell. 2010; 40(5):736-48. PubMed [journal]PMID: 21145482.
Loss of pRB causes centromere dysfunction and chromosomal instability. Manning AL, Longworth MS, Dyson NJ. Genes & development. 2010; 24(13):1364-76. PubMed [journal]PMID: 20551165 PMCID: PMC2895196.
pRb, a local chromatin organizer with global possibilities. Longworth MS, Dyson NJ. Chromosoma. 2010; 119(1):1-11. NIHMSID: NIHMS504344. PubMed [journal]PMID: 19714354 PMCID: PMC3760338.
RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Longworth MS, Herr A, Ji JY, Dyson NJ. Genes & development. 2008; 22(8):1011-24. PubMed [journal]PMID: 18367646 PMCID: PMC2335323.
Funded Postdoctoral Fellow Position
Job Description (PhD required):
Immediate opening for a funded Postdoctoral Fellow position in the Longworth Laboratory in the Department of Inflammation and Immunity at the Cleveland Clinic Lerner Research Institute. Candidate will be named a Lisa Dean Moseley fellow. Candidate will be expected to design, implement and manage research projects focused on newly discovered mechanisms that lead to the development of microcephaly in the fruitfly, Drosophila melanogaster. Individuals with experience and knowledge of techniques in neurodevelopment, molecular biology, Drosophila genetics, and biochemistry are encouraged to apply. Previous experience with human organoid-based systems is desired, but not required. Candidate must also be familiar with Western blotting, qRT-PCR, immunofluorescence assays, and various cloning techniques. Additional responsibilities include presenting research at institutional, national and international meetings, writing manuscripts, and contributing to the writing of grant applications.
Ph.D. with relevant laboratory experience is required. Proficiency in spoken and written English is required. Email cover letter with description of research interests, CV, and contact information for 3 references to: Michelle Longworth, Ph.D.; Department of Inflammation & Immunity; Lerner Research Institute, firstname.lastname@example.org.
With this funding, Drs. O’Connor and Longworth will investigate how host cells attempt to subvert human cytomegalovirus replication.