Dataset Information

Genetic alteration of histone lysine methyltransferases and their significance in renal cell carcinoma.

ABSTRACT:

Background

Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction. The genomic landscape and clinical significance of HMTs in renal cell carcinoma (RCC) remain uncovered.

Methods

We conducted an integrative analysis of 50 HMTs in RCC and discovered the internal relations among copy number alterations (CNAs), expressive abundance, mutations, and clinical outcome.

Results

We confirmed 12 HMTs with the highest frequency of genetic alterations, including seven HMTs with high-level amplification, two HMTs with somatic mutation, and three HMTs with putative homozygous deletion. Patterns of copy number and expression varied among different subtypes of RCC, including clear cell renal cell carcinoma, papillary cell carcinoma, and chromophobe renal carcinoma. Kaplan-Meier survival analysis and multivariate analysis identified that CNA or mRNA expression in some HMTs were significantly associated with shorter overall patient survival. Systematic analysis identified six HMTs (ASH1L, PRDM6, NSD1, EZH2, WHSC1L1, SETD2) which were dysregulated by genetic alterations as candidate therapeutic targets.

Discussion

In summary, our findings strongly evidenced that genetic alteration of HMTs may play an important role in generation and development of RCC, which lays a solid foundation for the mechanism for further research in the future.

SUBMITTER: Yan L

PROVIDER: S-EPMC6368835 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dynamic histone lysine methylation, regulated by methyltransferases and demethylases, plays fundamental roles in chromatin structure and gene expression in a wide range of eukaryotic organisms. A large number of SET-domain-containing proteins make up the histone lysine methyltransferase (HKMT) family, which catalyses the methylation of different lysine residues with relatively high substrate specificities. Another large family of Jumonji C (JmjC)-domain-containing histone lysine demethylases (JHDMs) reverses histone lysine methylation with both lysine site and methyl-state specificities. Through bioinformatic analysis, at least nine SET-domain-containing genes were found in the malaria parasite Plasmodium falciparum and its sibling species. Phylogenetic analysis separated these putative HKMTs into five subfamilies with different putative substrate specificities. Consistent with the phylogenetic subdivision, methyl marks were found on K4, K9 and K36 of histone H3 and K20 of histone H4 by site-specific methyl-lysine antibodies. In addition, most SET-domain genes and histone methyl-lysine marks displayed dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites. Furthermore, the malaria parasite and other apicomplexan genomes also encode JmjC-domain-containing proteins that may serve as histone lysine demethylases. Whereas prokaryotic expression of putative active domains of four P. falciparum SET proteins did not yield detectable HKMT activity towards recombinant P. falciparum histones, two protein domains expressed in vitro in a eukaryotic system showed HKMT activities towards H3 and H4, respectively. With the discovery of these Plasmodium SET- and JmjC-domain genes in the malaria parasite genomes, future efforts will be directed towards elucidation of their substrate specificities and functions in various cellular processes of the parasites.