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PMID: 16705169 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cathepsin L stabilizes the histone modification landscape on the Y chromosome and pericentromeric heterochromatin.

Molecular and cellular biology ·Vol. 26 ·No. 11 ·2006-06-00 ·Pages 4172-84

Bulynko YA, Hsing LC, Mason RW, Tremethick DJ, Grigoryev SA

Abstract

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.

MeSH Terms
Animals Cathepsin L Cathepsins/antagonists & inhibitors,deficiency,metabolism Cell Nucleus/metabolism Centromere/genetics Chromatin/genetics Chromosome Segregation/genetics Chromosomes, Mammalian/genetics Cysteine Endopeptidases/deficiency,metabolism DNA Methylation Epigenesis, Genetic Fibroblasts/cytology Gene Expression Genetic Markers Heterochromatin/genetics,metabolism Histones/metabolism Humans Lysine/metabolism Male Methyltransferases/genetics,metabolism Mice Mice, Knockout NIH 3T3 Cells Repressor Proteins/genetics,metabolism Thermodynamics Y Chromosome/genetics,metabolism
Chemicals
Chromatin Genetic Markers Heterochromatin Histones Repressor Proteins Suv39h1 protein, mouse Methyltransferases Cathepsins Cysteine Endopeptidases CTSL protein, human Cathepsin L Ctsl protein, mouse Lysine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bulynko Yaroslava A
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, USA.
Hsing Lianne C
Mason Robert W
Tremethick David J
Grigoryev Sergei A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00135-06
Published
2006-06-00
Pages
4172-84
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1489105
Subset
IM
Grants
NCRR NIH HHS · P20 RR020173 · United States
NCRR NIH HHS · 5P20RR020173 · United States
External Links
PubMed source DOI: 10.1128/MCB.00135-06 PMC Full Text View journal details
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