An NCI-designated Comprehensive Cancer Center
By Samantha Bonar | May 23, 2018
Diseases like cancer arise due to both changes in gene expression and cellular function. One important factor regulating gene expression and cellular function is called epigenetic modifications. Epigenetic modifications are inheritable changes not associated with changes in the DNA sequence.  Rather, epigenetic modifications include post-translational modifications (PTMs) of histone proteins and DNA methylation, regulating patterns of gene expression.
In an effort to understand the dynamic regulation of epigenetic modifications, a research group at City of Hope led by Binghui Shen, Ph.D., professor and chair in City of Hope’s Department of Cancer Genetics and Epigenetics, identified a novel enzyme activity of the JMJD1B gene known as arginine demethylase.
Arginine methylation of histone (H4R3me2s), an epigenetic modification, is carried out by the PRMT5 gene and has been implicated in various cellular processes including blood cancers. However, the enzymes that remove methyl group from histone arginine residue have not yet been reported in studies. The enzymes that deposit and remove these PTMs of histone proteins and DNA methylation are primary drug targets to alter specific pathways or gene expression to treat diseases such as cancer.
The research work, “JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells,” carried out by C, Shafat Ali and Xiaotao Duan (co-first author) at the Beckman Research Institute of City of Hope, was published in the April 10, 2018 issue of the journal Cell Reports.
In this study, the scientists reported for the first time that the JMJD1B gene is able to remove methyl group from histone arginine residues, H4R3me2s/H4R3me1. JMJD1B previously has been identified as removing methyl group from histone lysine residue, H3K9me2, and under almost similar conditions to catalyze demethylation. These histone methyl-arginine and methyl-lysine modifications act as suppressive markers for gene expression.
“Upregulation of arginine methylation is reported in many cancers and the studies are mainly focused on the function of protein arginine methyltransferases (PRTMs) due to the underexplored mechanisms of the arginine demethylation process,” said Ali.
“This study provides the possibility that arginine demethylases exist in the cells and are required to interplay with the function of PRMTs for normal cellular function.”
Using a mouse model, the researchers found that loss of the JMJD1B gene causes accumulation of methylated arginine/lysine residues of histones at different clusters of the genes and impairs activation of the genes involved in blood progenitor-cell development and differentiation. Consequently, these JMJD1B-deficient mice developed blood-cell disorders including an increase in white blood cells (lymphocytosis) and a decrease in red blood cells (mild anemia), and other phenotypes of myelodysplastic syndrome. In particular, the mice displayed a distinct blood cell lineage distribution, with an increase in the neutrophil cell population. The deregulated arginine-methylation level affects transcription factors signaling and the gene expression level of corresponding downstream signaling pathway genes.
This study discovered that active arginine demethylation process exists in eukaryotes and that JMJD1B demethylates both methylated arginine/lysine residue of histones for epigenetic programming of gene expression during blood-cell development and differentiation. These findings fill a fundamental gap in the understanding of dynamic regulation of arginine methylation level in cells and also provide therapeutic potential of the JMJDB1 gene for associated disorders.
“We believe that our study opens windows to conduct additional studies to help further understand the details of arginine-methylation regulation in diseases,” said Ali. “Thus, understanding the dynamic regulation of arginine-methylation level in the cells is cirtical to developing additional therapeutic targets to improve cancer cell response to current agents that work by regulating arginine-methylation lavel and gene expression.”