Dataset Information

Histidine methylation of MYLK2 and C3H zinc fingers by CARNMT1

ABSTRACT: We here describe our independent uncovering of CARNMT1 as a protein histidine methyltransferase (HMT), and our extensive efforts on defining its substrate specificity and methylation targets. We found that recombinant CARNMT1 methylated MYLK2-derived peptide containing His-148 in vitro. The recombinant CARNMT1 methylated also several proteins in extracts from CARNMT1 KO cells, and, using protein mass spectrometry, we identified several fully methylated CARNMT1 targets, all of which were C3H zinc finger (C3H ZnF) proteins. These included the previously identified U2AF1, ZC3H15 and ZC3H18, but also the novel substrates RBM22, PPP1R10, PRR3 and RNF113A. We also identified several of the homologous methylation events in Caenorhabditis elegans and showed that they could be introduced by the nematode CARNMT in vitro.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Caenorhabditis Elegans

SUBMITTER: Manuel Ramirez

LAB HEAD: Jedrzej Malecki

PROVIDER: PXD060821 | Pride | 2025-07-28

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Analysis_1_peptides_1_1_0.mzid	Mzid
	Analysis_2_peptides_1_1_0.mzid	Mzid
	Analysis_3_peptides_1_1_0.mzid	Mzid
	Analysis_4_peptides_1_1_0.mzid	Mzid
	Analysis_5_peptides_1_1_0.mzid	Mzid

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Publications

Identification of substrates and sequence requirements for CARNMT1-mediated histidine methylation of C3H zinc fingers.

Małecki Jędrzej M JM Weirich Sara S Ramirez-Garrastacho Manuel M Hagen Lars L Al-Egly Jakin J Anonsen Jan H JH Schroer Lisa L Herrera Maria C MC Davydova Erna E Slupphaug Geir G Jeltsch Albert A Falnes Pål Ø PØ

The Journal of biological chemistry 20250603 7

It has recently become clear that protein histidine methylation is widespread and functionally important in many cellular processes, and human CARNMT1 was recently reported as a novel protein histidine methyltransferase (HMT). We describe our independent uncovering of CARNMT1's protein HMT activity and a comprehensive assessment of its methylation targets and substrate specificity. Using a combination of in vitro methylation of cellular extracts and protein mass spectrometry, we identified sever ...[more]

PMID: 40473212

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Project description:Background: C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified. Methods: We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database. Results: We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5- aza-2'-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mstr1 and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC. Conclusions: Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC.