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Molecular and Cellular Biology, January 2008, p. 468-486, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01517-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Certain and Progressive Methylation of Histone H4 at Lysine 20 during the Cell Cycle{triangledown} ,{dagger}

James J. Pesavento,1,{ddagger} Hongbo Yang,3 Neil L. Kelleher,1,2,4 and Craig A. Mizzen3,4*

Center for Biophysics and Computational Biology,1 Department of Chemistry,2 Department of Cell and Developmental Biology,3 Institute for Genomic Biology, University of Illinois, Urbana, Illinois 618014

Received 21 August 2007/ Returned for modification 17 September 2007/ Accepted 16 October 2007

Methylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G2, M, and G1 phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.

* Corresponding author. Mailing address: Department of Cell and Developmental Biology, University of Illinois, B107 CLSL, MC123, 601 S. Goodwin Ave., Urbana, IL 61801. Phone: (217) 244-4896. Fax: (217) 244-1648. E-mail: cmizzen{at}life.uiuc.edu

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Dedicated to the memory of our good friend and colleague Tunji Toogun.

{ddagger} Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.

Molecular and Cellular Biology, January 2008, p. 468-486, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01517-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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