Abstract

Lysine Acetylation and Arginine Methylation of Histones are critical for Neural Differentiation and Memory: Probed by Small Molecule Modulators

Tapas Kundu, Professor, JNCASR

Eukaryotic genome is organized into a highly dynamic and ordered nucleoprotein structure, chromatin, which, along with DNA, is made of histones, non-histone proteins and non-coding RNA. Dynamic opening and closure of the chromatin fibre along with histone assembly and disassembly fine tune the spatio-temporal regulation of gene expression in most of the physiological phenomena including maintenance of pluripotency and differentiation. Covalent modification of histones, namely acetylation and arginine methylation have been shown to be important determinants in development and different lineage commitment. We have found that histone H3R17 methylation mediated by PRMT4/CARM1 is critical for astroglial lineage commitment in human embryonic stem cells as well as in zebrafish model. This effect may be regulated at various levels including the direct inhibition of H3R17 methylation or indirectly by dysregulated miRNAs downstream. On the other hand, using a novel histone acetyltransferase activator molecule, we find that p300/CBP mediated acetylation of histones is an important inducing factor for robust neurogenesis which presumably contributes to long-term spatial memory. These results will be discussed in the context of new small molecule based approaches to elucidate the role of epigenetic modifications in differentiation and stem cell research. These results also indicate at application of such molecules as therapeutic options in diseases.