Role of histone arginine methylation in Glial cell differentiation pathways and Cancer

Our laboratory has also been actively working on the small molecule modulators of chromatin modifying enzymes for more than a decade now. Apart from several small molecule inhibitors of lysine acetyltransferases and arginine methyltransferase, we have also discovered the first known small molecule activator of p300/CBP lysine acetyltransferase, which could activate histone acetylation in mice brain and thereby enhance the neurogenesis process and spatial memory. At present the mechanisms of p300/CBP activation and neurogenesis is one of the key interests of our group. Our laboratory has discovered new molecule to target, specific histone acetyl transferase PCAF and using this molecule, the gene network for muscle differentiation has been established. By employing one of the site specific inhibitors of the histone arginine methyl transferase CARM1, a new mechanism of glial differentiation has been shown by our group.

Since methylation is a part of epigenetic language, we investigated whether any histone methylation is also upregulated concomitantly in the oral cancer scenario.  Our histone methylation screening revealed that histone H3R17 asymmetric dimethylation mark is profoundly high in the cancerous tissue compared to the normal counterpart. We found that, indeed, the enzyme responsible for H3R17 asymmetric dimethylation, PRMT4/CARM1, is highly over-expressed in the malignant tumor. Mechanistically, it was found that transcription factor and oncogene YY1 ca upregulates the expression of CARM1/PRMT4, upon being methylated by the arginine methyltransferase (Behara A et al., 2019). We are currently investigating oral cancer's Ac-Rme (acetylation and arginine methylation) language.

1. Elucidation of glial differentiation pathway using small molecule inhibitor of PRMT4. (Fig. Ref.: Selvi BR et al., Mol Biol Cell, 2015)

2. A schematic to explain probable mechanisms of co-operative action between YY1 and CARM1 to either suppress or promote carcinogenesis by upregulating either YY1 responsive tumor suppressor genes (such as BRCA1, p53 and p73) or YY1 responsive oncogenes (such as c-Myc, c-Fos and Erb B2) respectively. (Fig. Ref.: Behera AK et al., Oncotarget, 2019)

1.      Selvi BR, Swaminathan A, Maheshwari U, Nagabhushana A, Mishra RK, Kundu TK. CARM1 regulates astroglial lineage through transcriptional regulation of Nanog and posttranscriptional regulation by miR92a. Mol Biol Cell. 2015;26(2):316-326.

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