Academic Background

Bill Theurkauf received his BA from Brandeis University in 1980, and his PhD in Biochemistry from Brandeis in 1988. From 1988 to 1993 he was a postdoctoral fellow in the Department of Biochemistry and Biophysics at UCSF, where he was supported by fellowships from the Damon Runyon-Walter Winchell Cancer Research Fund and NIH. From 1993 to 1998, he was a member of the faculty of the Department of Biochemistry and Cell Biology at the State University of New York at Stony Brook. In September 1998, Dr. Theurkauf joined the Program in Molecular Medicine at University of Massachusetts Medical Center as an associate professor. He is currently a professor in the Program in Molecular Medicine and Director of the Program in Cell and Developmental Dynamics

RESEARCH INTERESTS

The germline transmits the genetic instructions that perpetuate species, which presents unique pressures on genome maintenance systems. We’re interested in the mechanisms that maintain the integrity of the “immortal” genome during germline development, and in the developmental consequences of defects in these mechanisms.

piRNA PRODUCTION AND FUNCTION

Transposons and transposon fragments represent approximately half the human genome. Mobilization of these elements can lead to genetic instability and disease, but may also drive evolution and generate diversity during neurogenesis. In bilateral animals, Piwi-interacting RNAs (piRNAs) silence transposons during germline development and have a critical role in maintaining the integrity of the inherited genome. Primary piRNAs bind to PIWI clade Argonaute proteins and mediate transposon silencing. These small silencing RNAs are generated from long precursors encoded by heterochromatic clusters. Most of the piRNA processing machinery, by contrast, localizes to the perinuclear nuage. We would like to understand 1) the genetic and epigenetic mechanisms that specify clusters; 2) How transcripts from the heterochromatic piRNA clusters are directed to the biogenesis machinery/nuage, and 3) how piRNAs suppress transposition.

Related publications:

Klattenhoff, C. Bratu, D, P., McGinnis-Schultz, N., Koppetsch, B. S. , Cook, H. A., and Theurkauf, W. E. (2007). Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Developmental Cell 12, 45-56.

Li, C., Vagin, V. V., Lee, S., Xu, J., Ma, , Xi, H, Seitz, H., Horwich, M. D., Syrzycka, M., Honda, B. M., Kittler, E. L. W., Zapp, M. L., Klattenhoff, C., Schulz, N., Theurkauf, W. E., Weng, Z. and P. D. Zamore (2009). In the absence of Argonaute3, Aubergine-bound piRNAs collapse, but Piwi-bound piRNAs persist. Cell 137, 509-521.

Klattenhoff, C., Xi, H, Li, C, Lee, S., Xu, J., Khurana, J.S., Schultz, N., Koppetsch, B. S., Nowosielska, A., Seitz, H., Zamore, P.D., Weng. Z. and William E. Theurkauf (2009). The Drosophila HP1 homologue Rhino is required for transposon silencing and piRNA production by dual strand clusters. Cell 138, 1137-1149. PMID: 19732946.

Khurana, J. S., Xu. J., Weng, Z. and W. E. Theurkauf (2010). Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection. PLoS Genetics 6, e1001246.

TRANSPOSON CONTROL AND GENOME EVOLUTION

The piRNA pathway represents an adaptive immune system that controls the activity of mobile genetic elements. This rapidly evolving genome pathogens can arise from infectious viruses and spread through both interbreeding and poorly understood horizontal transfer mechanisms. We have recently found that introduction of P element transposons activates a broad spectrum of resident transposon families, and that silencing of the invading P element and resident elements is linked to generation of new transposon insertions in piRNA clusters that are transmitted through the germline with high fidelity. These findings indicate that adaptation to transposon invasion triggers significant structural changes in genome architecture that appear to genetically enhance silencing capacity. Ongoing studies are directed at understanding how invasion of a single transposon activates resident elements, and the role of this process in chromosome evolution.

Related publication:

Khurana, J. S., Wang, J., Xu, J., Koppetsch, B., Thomson, T., Nowosielska, A., Li., C., Zamore, P. D., Weng, Z., and W. E. Theurkauf (2011). Adaptation to P element transposon invasion in Drosophila melanogaster. Cell 147, 1551-1563.

DNA DAMAGE CONTROL OF DEVELOPMENTAL PROGRESSION

DNA damage checkpoint pathways have well-established roles in control of cell division and maintenance of genome integrity. Recent studies from a number of laboratories indicate that complex developmental processes are also regulated in response to DNA damage. In Drosophila, the axes of the embryo are specified through asymmetric localization of morphogenetic RNAs in the developing oocyte. During early embryogenesis, the maternally supplied RNAs that drive initial development are degraded and the genome of the zygotic is transcriptionally activated at the maternal-zygotic transition (MZT), which represents a switch in genetic control of development from the mother to the zygote. Axis specification and the MZT are controlled by DNA damage signaling through Chk2 kinase, which functions as a tumor suppressor in humans. We would like to understand how Chk2 governs these key developmental processes.

Related publications:

Klattenhoff, C. Bratu, D, P., McGinnis-Schultz, N., Koppetsch, B. S. , Cook, H. A., and Theurkauf, W. E. (2007). Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Developmental Cell 12, 45-56.

Benoit, B., He, C. H., Zhang, F., Votruba, S. M., Tadros, W., Weswood, J. T., Smibert, C. A., Lipshitz, H. D., and W. E. Theurkauf (2009). An essential role for the RNA-binding protein SMAUG at the Drosophila maternal-to-zygotic transition. Development 136, 923-932.