Gene dysregulation by histone variant H2A.Z in bladder cancer

Epigenetics & Chromatin

Woojin An¹  Peter W Laird²  Jin-Man Kim¹  Kyu Heo⁴  Jongkyu Choi¹  Vasu Punj³  Kyunghwan Kim¹ 

[1] Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, 1450 Biggy Street, Los Angeles, CA 90033, USA;USC Epigenome Center, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA;Bioinformatics Core and Division of Hematology, Norris Comprehensive Cancer Center, 1450 Biggy Street, Los Angeles, CA 90033, USA;Research Center, Dongnam Institute of Radiological and Medical Sciences, 40 Jwadong-gil, Gijang-gun, Busan 619-953, South Korea

关键词: Gene expression;    Microarray;    ChIP-seq;    Bladder cancer;    Chromatin;    H2A.Z;    Histone;   

Others  :  805328
DOI  :  10.1186/1756-8935-6-34

 received in 2013-06-06, accepted in 2013-09-27,  发布年份 2013

【 摘 要 】

Background

The incorporation of histone variants into nucleosomes is one of the main strategies that the cell uses to regulate the structure and function of chromatin. Histone H2A.Z is an evolutionarily conserved histone H2A variant that is preferentially localized within nucleosomes at the transcriptional start site (TSS). H2A.Z reorganizes the local chromatin structure and recruits the transcriptional machinery for gene activation. High expression of H2A.Z has been reported in several types of cancers and is causally linked to genomic instability and tumorigenesis. However, it is not entirely clear how H2A.Z overexpression in cancer cells establishes aberrant chromatin states and promotes gene expression.

Results

Through integration of genome-wide H2A.Z ChIP-seq data with microarray data, we demonstrate that H2A.Z is enriched around the TSS of cell cycle regulatory genes in bladder cancer cells, and this enrichment is correlated with the elevated expression of cancer-promoting genes. RNAi-mediated knockdown of H2A.Z in the cancer cells causes transcriptional suppression of multiple cell cycle regulatory genes with a distinct decrease in cell proliferation. H2A.Z nucleosomes around the TSS have higher levels of H3K4me2/me3, which coincides with the recruitment of two chromatin factors, WDR5 and BPTF. The observed recruitment is functional, as the active states of H2A.Z target genes are largely erased by suppressing the expression of WDR5 or BPTF, effects resembling H2A.Z knockdown.

Conclusions

We conclude that H2A.Z is overexpressed in bladder cancer cells and contributes to cancer-related transcription pathways. We also provide evidence in support of the engagement of H3K4me2/me3 and WDR5/BPTF in H2A.Z-induced cancer pathogenesis. Further studies are warranted to understand how H2A.Z overexpression contributes to the recruitment of the full repertoire of transcription machinery to target genes in bladder cancer cells.

【 授权许可】

   
2013 Kim et al.; licensee BioMed Central Ltd.

【 图 表 】

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