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Pamela Geyer, PhD

Portrait
Professor of Biochemistry
Professor of Obstetrics and Gynecology

Contact Information

Office
3135E MERF
Iowa City, IA 52242
319-335-6953

Lab
3159 MERF
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Education

BSc, McGill University
PhD, Ohio State University
Postdoctoral Fellow, Dept of Biology, Johns Hopkins University
Postdoctoral Fellow, Dept of Biology, Johns Hopkins University

Education/Training Program Affiliations

Department of Biochemistry PhD, Interdisciplinary Graduate Program in Genetics, Interdisciplinary Graduate Program in Molecular Medicine, Interdisciplinary Graduate Program in Neuroscience, Interdisciplinary Graduate Program in Translational Biomedicine, Medical Scientist Training Program

Center, Program and Institute Affiliations

Institute for Clinical and Translational Science

Research Summary

Nuclear architecture in stem cell survival and aging

Metazoan cells carry nuclei with diverse shapes and structures that reflect their distinct function. Nuclear structure depends upon proteins in the nuclear lamina (NL), a protein network comprised of lamins and hundreds of lamin associated proteins that line the inner nuclear membrane. NL proteins build contacts with the genome to regulate transcription, replication and DNA repair. In addition, these proteins transmit information between cellular compartments, by connecting the nucleoskeleton and cytoskeleton. Prominent changes in nuclear morphology occur during physiological aging and in disease. Indeed, mutations in genes encoding NL proteins cause a remarkable spectrum of age-enhanced human diseases, known as laminopathies. These diseases include muscular dystrophies, lipodystrophies, bone disorders, and accelerated aging disorders, such as progeria. Laminopathies have been linked to failures in adult stem cell maintenance, suggesting that NL proteins are critical for these processes.
We use Drosophila melanogaster as a model to understand NL contributions to adult stem cell maintenance in aging and disease. We study the family of NL proteins, called LEM-domain (LEM-D) proteins, a family defined by their shared interaction with Barrier-to-Autointegration Factor, a histone and DNA binding protein. The Drosophila LEM-D protein family includes three nuclear lamina proteins, D-emerin/Otefin, D-emerin2/Bocksbeutel and dMAN1. Our studies focus on D-emerin/Otefin and BAF because these proteins are required for maintenance of adult germline stem cells (GSCs) in the ovary. Indeed, we discovered that GSC death and blocked gametogenesis in d-emerin/ otefin and baf mutants are rescued by inactivation of two DNA damage response (DDR) kinases, ATR and Chk2. Surprisingly, activation of these DDR kinases is independent of canonical pathway triggers, such as DNA damage or replication stress. Instead, structural deformation of the NL appears to be a component of checkpoint activation. Despite remarkably normal oogenesis in d-emerin/otefin, chk2 double mutant ovaries, the rescued oocytes do not support embryogenesis, indicating these oocytes are defective. Such findings suggest that the NL checkpoint contributes to maintenance of gamete quality. Our current studies are focused on defining the molecular features of this checkpoint.

Our studies have a broad impact on understanding mechanisms responsible for loss of stem cells during physiological aging and age-dependent diseases. These states commonly are accompanied by changes in nuclear morphology that are associated with persistent DNA damage signaling. Thus, our studies have the potential to advance therapeutics that delay or eliminate pathologies that lead to stem cell loss.

Publications

Glenn, S. E., Geyer, P. K. (2019). Investigation of the developmental requirements of Drosophila HP1 and Insulator Partner Protein, HIPP1. G3: Genes, Genetics, Genomes, 9, 345-357.

Duan, T., Kitzman, S. C. & Geyer, P. K. (In Press). Survival of Drosophila germline stem cells requires the chromatin binding protein Barrier-to-autointegration factor.

Duan, T., Green, N., Tootle, T. L. & Geyer, P. K. (In Press). Nuclear architecture as an intrinsic regulator of female germline stem cell maintenance. Curr. Opin. Insect Sci., 37, 30-38. PMID: 32087561.

Duan, T., Geyer, P. K. (2018). Spermiogenesis and male fertility require the Suppressor of Hairy-wing in somatic cyst cells of Drosophila. Genetics, 209(3), 757-772.

Barton, L. J., Duan, T., Ke, W., Luttinger, A., Lovander, K. E., Soshnev, A. A. & Geyer, P. K. (In Press). Nuclear lamina dysfunction triggers a germline stem cell checkpoint. Nat. Commun..

Baxley, R. M., Bullard, J. D., Klein, M. W., Fell, A. G., Morales-Rosado, J. A., Duan, T., Geyer, P. K. (2017). Deciphering the DNA code for the function of the Drosophila polydactyl zinc finger protein Suppressor of Hairy-wing. Nucleic Acids Research, 45(8), 4463-4478. DOI: 10.1093/nar/gkx040.

Barton, L. J., Lovander, K. E., Pinto, B. S. & Geyer, P. K. (2016). Drosophila male and female germline stem cell niches require the nuclear lamina protein Otefin. Developmental biology, 415(1), 75-86. PMID: 27174470.

Berger, F., Geyer, P. K. (2016). Editorial overview: Genome architecture and expression: Connecting genome composition and nuclear architecture with function. (Vols. 37). pp. iv-vi. Current opinion in genetics & development. PMID: 27292868.

Barton, L. J., Soshnev, A. A. & Geyer, P. K. (2015). Networking in the nucleus: a spotlight on LEM-domain proteins. Current opinion in cell biology, 34, 1-8. PMID: 25863918.

Barton, L. J., Soshnev, A. A. & Geyer, P. K. (2015). Networking in the nucleus: A spotlight on LEM-domain proteins. Curr. Opin. Cell Biology, 34, 1-8.

Barton, L. J., Wilmington, S. R., Martin, M. J., Skopec, H. M., Lovander, K. E., Pinto, B. S. & Geyer, P. K. (2014). Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila. Genetics, 197(2), 653-65. PMID: 24700158.

Barton, L. J., Geyer, P. K. (2014). Stacking the deck for the next generation. (Vols. 81). pp. 481. Molecular Reproduction and Development.

Soshnev, A. A., Baxley, R. M., Manak, J. R., Tan, K. & Geyer, P. K. (2013). The insulator protein Suppressor of Hairy-wing is an essential transcriptional repressor in the Drosophila ovary. Development, 140(17), 3613-23. PMID: 23884443.

Barton, L. J., Pinto, B. S., Wallrath, L. L. & Geyer, P. K. (2013). The Drosophila nuclear lamina protein otefin is required for germline stem cell survival. Developmental cell, 25(6), 645-54. PMID: 23806619.

Hohl, A. M., Thompson, M., Soshnev, A. A., Wu, J., Morris, J., Hsieh, T. S., Wu, C. T. & Geyer, P. K. (2012). Restoration of topoisomerase 2 function by complementation of defective monomers in Drosophila. Genetics, 192(3), 843-56. PMID: 22923380.

Shoshnev, A. A., He, B., Baxley, R. M., Jiang, N., Hart, C. M., Tan, K. & Geyer, P. K. (2012). Genome-wide studies of the multi-zinc finger Drosophila Suppressor of Hairy-wing protein in the ovary. Nucleic Acids Research, 40(12). PMID: 22406832.

Soshnev, A. A., Ishimoto, H., McAllister, B. F., Li, X., Wehling, M. D., Kitamoto, T. & Geyer, P. K. (2011). A conserved long noncoding RNA affects sleep behavior in Drosophila. Genetics, 189(2), 455-68. PMID: 21775470.

Baxley, R. M., Soshnev, A. A., Koryakov, D. E., Zhimulev, I. F. & Geyer, P. K. (2011). The role of the Suppressor of Hairy-wing insulator protein in Drosophila oogenesis. Developmental biology, 356(2), 398-410. PMID: 21651900.

Geyer, P. K., Vitalini, M. W. & Wallrath, L. L. (2011). Nuclear organization: taking a position on gene expression. Current opinion in cell biology, 23(3), 354-9. PMID: 21450447.

Dialynas, G., Speese, S., Budnik, V., Geyer, P. K. & Wallrath, L. L. (2010). The role of Drosophila Lamin C in muscle function and gene expression. Development (Cambridge, England), 137(18), 3067-77. PMID: 20702563.

Schulze, S. R., Curio-Penny, B., Speese, S., Dialynas, G., Cryderman, D. E., McDonough, C. W., Nalbant, D., Petersen, M., Budnik, V., Geyer, P. K. & Wallrath, L. L. (2009). A comparative study of Drosophila and human A-type lamins. PloS one, 4(10), e7564. PMID: 19855837.

Wallrath, L. L., Nagy, P. L. & Geyer, P. K. (2008). Epigenetics of development and human disease. (Vols. 647). pp. 1-2. Mutation research. PMID: 18983859.

Pinto, B. S., Wilmington, S. R., Hornick, E. E., Wallrath, L. L. & Geyer, P. K. (2008). Tissue-specific defects are caused by loss of the Drosophila MAN1 LEM domain protein. Genetics, 180(1), 133-45. PMID: 18723885.

Kuhn-Parnell, E. J., Helou, C., Marion, D. J., Gilmore, B. L., Parnell, T. J., Wold, M. S. & Geyer, P. K. (2008). Investigation of the properties of non-gypsy suppressor of hairy-wing-binding sites. Genetics, 179(3), 1263-73. PMID: 18562648.

Soshnev, A. A., Li, X., Wehling, M. D. & Geyer, P. K. (2008). Context differences reveal insulator and activator functions of a Su(Hw) binding region. PLoS genetics, 4(8), e1000159. PMID: 18704163.

Baxley, R. M., Geyer, P. K. (2008). The role of insulators in genome organization and gene expression. The Encyclopedia of Life Sciences, John Wiley & Sons.

Wallrath, L. L., Nagy, P. L., Geyer, P. K. (2008). Editorial. Epigenetics of Development and Human Disease. (Vols. 1). (647), pp. 1-2. Mutation Research. PMID: 18983859.

Geyer, P. K., Wallrath, L. L. (2007). Heterochromatin: not just for silencing anymore: report of the Eighth International Conference on Drosophila Heterochromatin. Fly, 1(4), 251-6. PMID: 18820453.

Golovnin, A., Mazur, A., Kopantseva, M., Kurshakova, M., Gulak, P. V., Gilmore, B. L., Whitfield, W., Geyer, P. K., Pirrotta, V. & Georgiev, P. (2007). Integrity of the Mod(mdg4)-67.2 BTB domain is critical to insulator function in Drosophila. Molecular and cellular biology, 27, 963-974. PMID: 17101769.

Parnell, T. J., Kuhn, E. J., Gilmore, B. L., Helou, C., Wold, M. S. & Geyer, P. K. (2006). Identification of genomic sites that bind the Drosophila suppressor of Hairy-wing insulator protein. Molecular and cellular biology, 26(16), 5983-93. PMID: 16880510.

Wallrath, L. L., Geyer, P. K. (2006). TFIIIC boxes in the genome. Cell, 125(5), 829-31. PMID: 16751090.

Drapeau, M. D., Cyran, S. A., Viering, M. M., Geyer, P. K. & Long, A. D. (2006). A cis-regulatory sequence within the yellow locus of Drosophila melanogaster required for normal male mating success. Genetics, 172(2), 1009-30. PMID: 16272418.

Schulze, S. R., Curio-Penny, B., Li, Y., Imani, R. A., Rydberg, L., Geyer, P. K. & Wallrath, L. L. (2005). Molecular genetic analysis of the nested Drosophila melanogaster lamin C gene. Genetics, 171(1), 185-96. PMID: 15965247.

Kuhn, E. J., Hart, C. M. & Geyer, P. K. (2004). Studies of the role of the Drosophila scs and scs' insulators in defining boundaries of a chromosome puff. Molecular and cellular biology, 24(4), 1470-80. PMID: 14749365.

Wallrath, L. L., Danzer, J. R., Yazgan, O. & Geyer, P. K. (2004). Nuclear organization, chromatin structure and gene silencing. in Encyclopedia of Biological Chemistry, Elsevier, Oxford, 3, 105-108.

Parnell, T. J., Viering, M. M., Skjesol, A., Helou, C., Kuhn, E. J. & Geyer, P. K. (2003). An endogenous suppressor of hairy-wing insulator separates regulatory domains in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 100(23), 13436-41. PMID: 14597701.

Kuhn, E. J., Geyer, P. K. (2003). Genomic insulators: connecting properties to mechanism. Current opinion in cell biology, 15(3), 259-65. PMID: 12787766.

Kuhn, E. J., Viering, M. M., Rhodes, K. M. & Geyer, P. K. (2003). A test of insulator interactions in Drosophila. The EMBO journal, 22(10), 2463-71. PMID: 12743040.

Parnell, T. J., Grade, S. K., Geyer, P. K. & Wallrath, L. L. (2003). Position-effect variegation in human genetic disease. Encyclopedia of the Human Genome. John Wiley & Sons, Ltd, 4, 642-46.

Geyer, P. K., Clark, I. (2002). Protecting against promiscuity: the regulatory role of insulators. Cellular and molecular life sciences : CMLS, 59(12), 2112-27. PMID: 12568337.

Chen, J. L., Huisinga, K. L., Viering, M. M., Ou, S. A., Wu, C. T. & Geyer, P. K. (2002). Enhancer action in trans is permitted throughout the Drosophila genome. Proceedings of the National Academy of Sciences of the United States of America, 99(6), 3723-8. PMID: 11904429.

Roseman, R. R., Morgan, K., Mallin, D. R., Roberson, R., Parnell, T. J., Bornemann, D. J., Simon, J. A. & Geyer, P. K. (2001). Long-range repression by multiple polycomb group (PcG) proteins targeted by fusion to a defined DNA-binding domain in Drosophila. Genetics, 158(1), 291-307. PMID: 11333237.

Kuhn, E., Geyer, P. K. (2001). Boundary Elements. Encyclopedia of Molecular Medicine, John Wiley & Sons.

Geyer, P. K., Parnell, T. J. (2001). Chromosomes: Higher order organization. Encyclopedia of Life Sciences. London: Naturing Publishing Group.

Parnell, T. J., Geyer, P. K. (2000). Differences in insulator properties revealed by enhancer blocking assays on episomes. The EMBO journal, 19(21), 5864-74. PMID: 11060037.

Scott, K. C., Taubman, A. D. & Geyer, P. K. (1999). Enhancer blocking by the Drosophila gypsy insulator depends upon insulator anatomy and enhancer strength. Genetics, 153(2), 787-98. PMID: 10511558.

Morris, J. R., Geyer, P. K. & Wu, C. T. (1999). Core promoter elements can regulate transcription on a separate chromosome in trans. Genes & development, 13(3), 253-8. PMID: 9990850.

Morris, J. R., Chen, J. L., Filandripos, S. T., Dunn, R. C., Fisk, R., Geyer, P. K. & Wu, C. T. (1999). An Analysis of Transvection at the yellow locus of Drosophila melanogaster. Genetics,(151), 633-651.

Morris, J. R., Chen, J. L., Geyer, P. K. & Wu, C. T. (1998). Two modes of transvection: enhancer action in trans and bypass of a chromatin insulator in cis. Proceedings of the National Academy of Sciences of the United States of America, 95(18), 10740-5. PMID: 9724774.

Mallin, D. R., Myung, J. S., Patton, J. S. & Geyer, P. K. (1998). Polycomb group repression is blocked by the Drosophila suppressor of Hairy-wing [su(Hw)] insulator. Genetics, 148(1), 331-9. PMID: 9475743.

Geyer, P. K. (1997). The role of insulator elements in defining domains of gene expression. Current opinion in genetics & development, 7(2), 242-8. PMID: 9115431.

Scott, K. S., Geyer, P. K. (1995). Effects of the su(Hw) insulator protein on the expression of the divergently transcribed Drosophila yolk protein genes. The EMBO journal, 14(24), 6258-67. PMID: 8557045.

Roseman, R. R., Swan, J. M. & Geyer, P. K. (1995). A Drosophila insulator protein facilitates dosage compensation of the X chromosome min-white gene located at autosomal insertion sites. Development (Cambridge, England), 121(11), 3573-82. PMID: 8582271.

Roseman, R. R., Johnson, E. A., Rodesch, C. K., Bjerke, M., Nagoshi, R. N. & Geyer, P. K. (1995). A P element containing suppressor of hairy-wing binding regions has novel properties for mutagenesis in Drosophila melanogaster. Genetics, 141(3), 1061-74. PMID: 8582613.

Rodesch, C., Geyer, P. K., Patton, J. S., Bae, E. & Nagoshi, R. N. (1995). Developmental analysis of the ovarian tumor gene during Drosophila oogenesis. Genetics, 141(1), 191-202. PMID: 8536967.

Nagoshi, R. N., Patton, J. S., Bae, E. & Geyer, P. K. (1995). The somatic sex determines the requirement for ovarian tumor gene activity in the proliferation of the Drosophila germline. Development (Cambridge, England), 121(2), 579-87. PMID: 7768194.

Bae, E., Cook, K. R., Geyer, P. K. & Nagoshi, R. N. (1994). Molecular characterization of ovarian tumors in Drosophila. Mechanisms of development, 47(2), 151-64. PMID: 7811638.

Geyer, P. K., Patton, J. S., Rodesch, C. & Nagoshi, R. N. (1993). Genetic and molecular characterization of P element-induced mutations reveals that the Drosophila ovarian tumor gene has maternal activity and a variable null phenotype. Genetics, 133(2), 265-78. PMID: 8436275.

Roseman, R. R., Pirrotta, V. & Geyer, P. K. (1993). The su(Hw) protein insulates expression of the Drosophila melanogaster white gene from chromosomal position-effects. The EMBO journal, 12(2), 435-42. PMID: 8382607.

Patton, J. S., Gomes, X. V. & Geyer, P. K. (1992). Position-independent germline transformation in Drosophila using a cuticle pigmentation gene as a selectable marker. Nucleic acids research, 20(21), 5859-60. PMID: 1333590.

Geyer, P. K., Corces, V. G. (1992). DNA position-specific repression of transcription by a Drosophila zinc finger protein. Genes & development, 6(10), 1865-73. PMID: 1327958.

Geyer, P. K., Chien, A. J., Corces, V. G. & Green, M. M. (1991). Mutations in the su(s) gene affect RNA processing in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America, 88(16), 7116-20. PMID: 1714588.

Corces, V. G., Geyer, P. K. (1991). Interactions of retrotransposons with the host genome: the case of the gypsy element of Drosophila. Trends in genetics : TIG, 7(3), 86-90. PMID: 1851585.

Geyer, P. K., Green, M. M. & Corces, V. G. (1990). Tissue-specific transcriptional enhancers may act in trans on the gene located in the homologous chromosome: the molecular basis of transvection in Drosophila. The EMBO journal, 9(7), 2247-56. PMID: 2162766.

Harrison, D. A., Geyer, P. K., Spana, C. & Corces, V. G. (1989). The gypsy retrotransposon of Drosophila melanogaster: mechanisms of mutagenesis and interaction with the suppressor of Hairy-wing locus. Developmental genetics, 10(3), 239-48. PMID: 2472241.

Geyer, P. K., Richardson, K. L., Corces, V. G. & Green, M. M. (1988). Genetic instability in Drosophila melanogaster: P-element mutagenesis by gene conversion. Proceedings of the National Academy of Sciences of the United States of America, 85(17), 6455-9. PMID: 2842772.

Geyer, P. K., Green, M. M. & Corces, V. G. (1988). Reversion of a gypsy-induced mutation at the yellow (y) locus of Drosophila melanogaster is associated with the insertion of a newly defined transposable element. Proceedings of the National Academy of Sciences of the United States of America, 85(11), 3938-42. PMID: 2836866.

Geyer, P. K., Green, M. M. & Corces, V. G. (1988). Induction of Mutant Phenotypes by a Drosophila melanogaster Retrotransposon Requires Sequences Homologous to Mammalian Enhancers. Proceedings of the National Academy of Sciences, 85, 8593-8597.

Geyer, P. K., Corces, V. G. (1987). Separate regulatory elements are responsible for the complex pattern of tissue-specific and developmental transcription of the yellow locus in Drosophila melanogaster. Genes & development, 1(9), 996-1004. PMID: 3123324.

Geyer, P. K., Green, M. M. & Corces, V. G. (1987). Molecular basis of transposable element-induced mutations in Drosophila melanogaster. Eukaryotic Transposable Elements as Mutagenic Agents: CSHLP, Cold Spring Harbor, N.Y.

Geyer, P. K., Fyrberg, E. A. (1986). 5'-flanking sequence required for regulated expression of a muscle-specific Drosophila melanogaster actin gene. Molecular and cellular biology, 6(10), 3388-96. PMID: 3025590.

Geyer, P. K., Spana, C. & Corces, V. G. (1986). On the molecular mechanism of gypsy-induced mutations at the yellow locus of Drosophila melanogaster. The EMBO journal, 5(10), 2657-62. PMID: 3096713.

Jenh, C. H., Geyer, P. K. & Johnson, L. F. (1985). Control of thymidylate synthase mRNA content and gene transcription in an overproducing mouse cell line. Molecular and cellular biology, 5(10), 2527-32. PMID: 3837178.

Jenh, C. H., Geyer, P. K., Baskin, F. & Johnson, L. F. (1985). Thymidylate synthase gene amplification in fluorodeoxyuridine-resistant mouse cell lines. Molecular pharmacology, 28(1), 80-5. PMID: 2991733.

Geyer, P. K., Johnson, L. F. (1984). Molecular cloning of DNA sequences complementary to mouse thymidylate synthase messenger RNA. The Journal of biological chemistry, 259(11), 7206-11. PMID: 6144683.

Geyer, P. K., Meyuhas, O., Perry, R. P. & Johnson, L. F. (1982). Regulation of ribosomal protein mRNA content and translation in growth-stimulated mouse fibroblasts. Molecular and cellular biology, 2(6), 685-93. PMID: 14582163.