Stephen A. Krawetz, Ph.D.
Charlotte B. Failing Professor

253 C. S. Mott
275 East. Hancock
Detroit, MI 48201
Voice: 313-577-6770
FAX: 313-577-8554
Home Page: compbio.med.wayne.edu
steve@compbio.med.wayne.edu
 
Charlotte B. Failing Professor (also with Obstetrics and Gynecology and the Institute for Scientific Computing); Ph.D., Toronto, 1983.

Research Goal

To achieve a Systems Biology.level understanding of the genetic mechanism(s) that controls the selection of genes for development and differentiation.

Current Research Program

We have directed our studies toward defining how gene loci are selected for expression by the mechanism termed potentiation, i.e., the opening of chromatin domains. Understanding the selective expression of our genome is fundamental to achieving the ability to reprogram our genome, the ultimate self-help therapeutic. My laboratory is using the endogenous and transgenic human and mouse protamine gene clusters as model systems of chromatin mediated differentiation. The epigenetic studies that we are pursuing extend from nuclear structure - histone modification to the role of non coding RNAs as modulators of gene expression. Determining how these multiple levels of control interact and feedback to the genome to modulate chromatin structure and thus transcription is currently being explored at the genome-wide systems level. We continue to use and develop state-of-the-art technologies that now include expression and ChIP based microarrays alongside deep sequencing using Illumina (GA2) and LS (454). A single experiment now yields over 10,000,000 data points. This data rich environment requires us to continually develop novel analysis tools while extending our computational capacity. The use of pipelining - grid computing and other strategies for high throughput bioinformatic analyses will help draw together our understanding of gene expression and chromatin structure. We are beginning to uncover the complex set of processes that lead to successful conception and a healthy child. These incorporate both the genetic and epigenetic impactors of the fetal onset of adult disease, including the delivery of spermatozoon RNAs at fertilization. This population of RNAs is likely to provide an essential component of early paternal genome reprogramming. By understanding the system of chromatin structure and how associations with nuclear organizers affect transcript regulation, we will provide a key to unlocking the mechanism of genome reprogramming. With the ability to use of one’s own genome, this will certainly help bring self-help therapeutics, like gene therapy, from the bench to the bedside.

Selected Publications

Reprogramming:

Heng, H.Q.H., Goetze, S., Ye, C.J., Liu, G., Stevens, J.B., Bremer, S.W., Wykes, S.M., Bode, J. and Krawetz, S. A. (2004) Chromatin loops are selectively anchored using scaffold/matrix-attachment regions. Journal of Cell Science 117:999-1008.

Martins, R.P., Ostermeier, G.C. and Krawetz, S.A. (2004) Nuclear matrix interactions at the human protamine domain: a working model of potentiation. Journal of Biological Chemistry 279:51862-51868.

Linnemann, A.K., Platts, A.E., Doggett, N., Gluch, A., Bode, J. and Krawetz S. A. (2007) Genome wide identification of nuclear matrix attachment regions: an analysis of methods. Biochemical Society Transactions. 35:612-617.

Martins, R. P. and Krawetz, S.A. (2007) Decondensing the protamine domain for transcription. Proceedings of the National Academy of Sciences (U.S.A.) 104:8340-8345.

Ottaviani, D, Lever, E., Mitter, R, Jones, T. Forshew, T., Christova, R., Tomazou, E., Rakyan, V.K., Krawetz, S.A., Platts, A.E., Segarane, B., Beck, S. and Sheer, D. (In Press) Reconfiguration of Genomic Anchors upon Transcriptional Activation of the Human Major Histocompatibility Complex. Genome Research.

Sperm RNA delivery:

Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA profiles of normal fertile men. The Lancet. 360:773-777.

Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. and Krawetz, S.A. (2004) Delivering spermatozoan RNA to the oocyte. Nature 429:154.

Krawetz, S.A. (2005) Paternal Contribution: new insights and future challenges. Nature Reviews Genetics 6:633-642.

Platts, A.E., Dix, D. J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J. C., Rawe, V.Y., Quintana, S., Diamond, M.P., Strader, L.F. and Krawetz, S.A. (2007) Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Human Molecular Genetics. 16:763-773.

Lalancette, C., Miller, D., Li, Y. and Krawetz, S. A. (2008) Paternal contributions: new functional insights for spermatozoal RNA. Journal of Cellular Biochemistry 35th Anniversary issue. 104:1570-1579.

Bioinformatics:

Platts, A.E., Quayle, A.K. and Krawetz, S.A. (2006). In-Silico Prediction and Observations of Nuclear Matrix Attachment. Cellular and Molecular Biology Letters 11:191-213.

Fayz, B., Moldenhauer, J.S., Wang, D., Zhao, G., Yao, B., Liu, D., Weinsheimer, S., Gardner, L., Johnson, A., Womble D.D. and Krawetz, S.A. (2005) LARALink: A web application for cytogenetic linkage analysis. Clinical Genetics. 67:314-321.

Naismith, L., Lalancette, C., Platts, A.E., and Krawetz, S.A. (2008) The KLAB Toolbox: A suite of in-house software applications for epigenetic analysis. SBiRM: Systems Biology in Reproductive Medicine. 54:97-108.

Platts, A. E. Johnson, G.D., Linnemann, A.K., and Krawetz, S.A. (2008) Real-Time PCR Quantification Using A Variable Reaction Efficiency Mode. Analytical Biochemistry. 380:315-322.

Lalancette, C., Platts, A.E., Lu, Y., Lu, S. and Krawetz, S.A. (2008) Computational Identification Of Transcription Frameworks of Early Committed Spermatogenic Genes. Molecular Genetics and Genomics. 280:263-274.

 

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