Winship Herr, Professor
|Winship Herr received his PhD from Harvard University in 1982 for studies on recombinant retroviruses in leukemogenic mice with Walter Gilbert. After postdoctoral studies with Frederick Sanger in Cambridge England and Joe Sambrook at Cold Spring Harbor Laboratory, he joined the Cold Spring Harbor Laboratory faculty in 1984. There he served as assistant director of the Laboratory from 1994-2002 and from 1998-2004 was the founding dean of the Watson School of Biological Sciences, a doctoral degree-granting school. He arrived at the CIG in September 2004. Winship Herr is EMBO member since 2008 and also director of the "Ecole de biologie" since August 1st, 2009.
Cell-cycle; differentiation; transcription; herpes simplex virus; cancer
Two complete sets of instructions contained within the genomes we inherit from our parents are responsible for directing a single cell - the zygote - to become an adult human being. This process results from controlled patterns of gene expression that are maintained as well as changed during many rounds of cell division, differentiation, and death. Control of gene transcription is fundamental to these processes, with genetic and epigenetic defects in transcriptional regulation often leading to human disease including cancer.
To investigate these processes, we study a key regulator of human-cell proliferation that is also implicated in embryonic stem cell maintenance and cancer. This protein, called HCF-1 for herpes simplex virus host-cell factor-1, binds to many promoters by recognizing site-specific DNA-binding proteins and recruits histone-modifying activities [e.g., Sin3 histone deacetylase and mixed-lineage leukemia (MLL) family of histone methyltransferases] for activation and repression of transcription. After synthesis, HCF-1 undergoes an unusual process of proteolytic maturation that creates associated N- and C-terminal subunits. These subunits regulate different phases of the human cell cycle: The N-terminal subunit permits cells to progress into S phase for genome replication by associating with the E2F family of cell-cycle regulators. The C-terminal subunit is required for proper segregation of the replicated genome into the two daughter cells in M phase.
HCF-1 function is conserved in animals. We have taken advantage of this property to perform genetic, genomic, biochemical, bioinformatic, and molecular studies in diverse organisms including the C. elegans worm, Drosophila fruit fly, mouse, and human. This strategy takes advantage of the post-genome era in which we have available the complete sets of instructions for many species and can therefore compare and contrast the functions of conserved molecules such as HCF-1 in different life contexts. Our interdisciplinary approach using diverse biological systems provides an exciting intellectual environment to pursue an understanding of the regulation of cell proliferation and differentiation.
Lazarus, M.B., Jiang, J., Kapuria, V., Bhuiyan, T., Janetzko, J., Zandberg, W.F., Vocadlo, D.J., Herr, W., and Walker, S. (2013) HCF-1 is cleaved in the active site of O-GlcNAc transferase. Science 342, 1235–1239.
Michaud, J., Praz, V., James Faresse, N., JnBaptiste, C.K., Tyagi, S., Schütz, F., and Herr, W. (2013) HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy. Genome Res. 23, 907–916.
Park, J., Lammers, F., Herr, W., and Song, J.-J. (2012) HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation. Proc Natl Acad Sci U S A. 109: 17430-17435.
Le Martelot, G., Canella, D., Symul, L., Migliavacca, E., Gilardi, F., Liechti, R., Martin, O., Harshman, K., Delorenzi, M., Desvergne, B., Herr, W., Deplancke, B., Schibler, U., Rougemont, J., Guex, N., Hernandez, N., Naef, F. and CycliX Consortium. (2012) Genome-wide RNA polymerase II profiles and RNA accumulation reveal kinetics of transcription and associated epigenetic changes during diurnal cycles. PLoS Biol. 10, e1001442.
Capotosti, F., Guernier, S., Lammers, F., Waridel, P., Cai, Y., Jin, J. Conaway, J.W., Conaway, R.C., and Herr, W. (2011) O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1. Cell 144: 376-388.