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J. Biol. Chem., Vol. 282, Issue 18, 13854-13863, May 4, 2007

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Genome-wide Analysis of Histone Lysine Methylation Variations Caused by Diabetic Conditions in Human Monocytes^*

Feng Miao, Xiwei Wu, Lingxiao Zhang, Yate-Ching Yuan, Arthur D. Riggs^¶, and Rama Natarajan¹

From the Departments of Diabetes, Biomedical Informatics, and ^¶Biology, Beckman Research Institute of City of Hope, Duarte, California 91010

Aberrant histone lysine methylation patterns that change chromatin structure can promote dysregulated gene transcription and disease progression. Diabetic conditions such as high glucose (HG) are known to alter key pathologic pathways. However, their impact on cellular histone lysine methylation is unknown. We hypothesized that chronic HG can induce aberrant changes in histone H3 lysine 4 and lysine 9 dimethylation (H3K4me2 and H3K9me2) within target cells. Chromatin immunoprecipitation linked to microarrays (ChIP-on-chip) is currently a widely used approach for acquiring genome-wide information on histone modifications. We adopted this approach to profile and compare the variations in H3K4me2 and H3K9me2 in human gene coding and CpG island regions in THP-1 monocytes cultured in normal glucose and HG. Subsequently, we identified key relevant candidate genes displaying differential changes in H3K4me2 and H3K9me2 in HG versus normal glucose and also validated them with follow-up conventional ChIPs. Relevance to human diabetes was demonstrated by noting that H3K9me2 at the coding and promoter regions of two candidate genes was significantly greater in blood monocytes of diabetic patients relative to normal controls similar to the THP-1 data. In addition, regular mRNA profiling with cDNA arrays revealed correlations between mRNA and H3K9me2 levels. These novel results show histone methylation variations, for the first time, under diabetic conditions at a genome-wide level.

Received for publication, October 5, 2006 , and in revised form, February 21, 2007.

^* This work was supported by grants from the Juvenile Diabetes Research Foundation and NIDDK and NHLBI from the National Institutes of Health and in part by a General Clinical Research Center, National Center for Research Resources Grant NCRR MO1RR00043 (to City of Hope). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 3-11.

¹ To whom correspondence should be addressed: 1500 East Duarte Rd., Duarte, CA 91010. Tel.: 626-256-4673 (ext. 62289); Fax: 626-301-8136; E-mail: RNatarajan{at}coh.org.

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				F. Miao, X. Wu, L. Zhang, A. D. Riggs, and R. Natarajan Histone Methylation Patterns Are Cell-Type Specific in Human Monocytes and Lymphocytes and Well Maintained at Core Genes J. Immunol., February 15, 2008; 180(4): 2264 - 2269. [Abstract] [Full Text] [PDF]