Michelle S. Longworth, PhD
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
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:
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
For more information, check out our lab website at https://longworthlab.com/
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.
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
Ray G, Longworth MS.
Inflamm Bowel Dis. 2019 Jan 10;25(2):235-247. doi: 10.1093/ibd/izy330.
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]
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.
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.
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