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Molecular and Cellular Biology, June 2006, p. 4172-4184, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.00135-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin{dagger}

Yaroslava A. Bulynko,1 Lianne C. Hsing,2 Robert W. Mason,3 David J. Tremethick,4 and Sergei A. Grigoryev1*

Penn State University College of Medicine, Department of Biochemistry and Molecular Biology, H171, Milton S. Hershey Medical Center, P.O. Box 850, 500 University Drive, Hershey, Pennsylvania 17033,1 Department of Immunology, Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington 98195,2 Department of Biomedical Research, Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, Delaware 19803,3 The John Curtin School of Medical Research, The Australian National University, P.O. Box 334, Canberra, Australian Capital Territory 2601, Australia4

Received 23 January 2006/ Returned for modification 23 February 2006/ Accepted 7 March 2006

Posttranslational histone modifications and histone variants form a unique epigenetic landscape on mammalian chromosomes where the principal epigenetic heterochromatin markers, trimethylated histone H3(K9) and the histone H2A.Z, are inversely localized in relation to each other. Trimethylated H3(K9) marks pericentromeric constitutive heterochromatin and the male Y chromosome, while H2A.Z is dramatically reduced at these chromosomal locations. Inactivation of a lysosomal and nuclear protease, cathepsin L, causes a global redistribution of epigenetic markers. In cathepsin L knockout cells, the levels of trimethylated H3(K9) decrease dramatically, concomitant with its relocation away from heterochromatin, and H2A.Z becomes enriched at pericentromeric heterochromatin and the Y chromosome. This change is also associated with global relocation of heterochromatin protein HP1 and histone H3 methyltransferase Suv39h1 away from constitutive heterochromatin; however, it does not affect DNA methylation or chromosome segregation, phenotypes commonly associated with impaired histone H3(K9) methylation. Therefore, the key constitutive heterochromatin determinants can dynamically redistribute depending on physiological context but still maintain the essential function(s) of chromosomes. Thus, our data show that cathepsin L stabilizes epigenetic heterochromatin markers on pericentromeric heterochromatin and the Y chromosome through a novel mechanism that does not involve DNA methylation or affect heterochromatin structure and operates on both somatic and sex chromosomes.

* Corresponding author. Mailing address: Penn State University College of Medicine, Department of Biochemistry and Molecular Biology, H171, Milton S. Hershey Medical Center, P.O. Box 850, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-8588. Fax: (717) 531-7072. E-mail: sag17{at}psu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2006, p. 4172-4184, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.00135-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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