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. Since his arrival, he has been vice-dean for biological sciences (2007–2009) and director of the School of Biology (2009–2015) of the Faculty of Biology and Medicine. Winship Herr is EMBO member since 2008.
Molecular epigenetics; 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, differentiation and cobalamin (a.k.a. vitamin B12) metabolism — it is also implicated in 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., histone deacetylase and methyltransferases) for activation and repression of transcription. After synthesis, HCF-1 undergoes an unusual process of maturation in which it is cleaved by the O-linked N-acetyl glucosamine transferase OGT, creating 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, for example, 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 take advantage of this property to perform genetic, genomic, biochemical, bioinformatic, and molecular studies in diverse organisms concentrating now on mouse, where we focus on liver function, and human, where we use tissue culture cells and CRISPR/Cas9 directed mutagenesis. 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 human gene transcription.
Kapuria, V., Röhrig, U.T., Bhuiyan, T., Borodkin, V.S., van Aalten, D.M.F., Zoete, V. and Herr, W. (2016) Proteolysis of HCF-1 by glycosylation-incompetent O-GlcNAc transferase:UDP-GlcNAc complexes. Genes Dev. 30, 960–972.
Minocha, S., Sung, T.-L., Villeneuve, D., Lammers, F. and Herr, W. (2016) Compensatory embryonic response to allele-specific inactivation of the murine X-linked gene Hcfc1. Dev. Biol. 412, 1–17.
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.
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.
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