CARM1 regulates astroglial lineage through transcriptional regulation of Nanog and posttranscriptional regulation by miR92a.
Coactivator-associated arginine methyltransferase (CARM1/PRMT4)-mediated transcriptional coactivation and arginine methylation is known to regulate various tissue-specific differentiation events. Although CARM1 is expressed in the neural crest region in early development, coinciding with early neuronal progenitor specification, the role of CARM1 in any neuronal developmental pathways has been unexplored. Using a specific small-molecule inhibitor of CARM1-mediated H3R17 methylation in human embryonic stem cell line, we find that H3R17 methylation contributes to the maintenance of the astroglial cell population. A network of regulation was observed on the miR92a promoter by which H3R17-responsive Nanog bound to the miR92a promoter decreased upon inhibition, resulting in an abnormal gene expression program influencing the glial lineage. This was also true in zebrafish, in which, with the help of CARM1 inhibitor and CARM1 morpholinos, we show that inhibition of H3R17 methylation results in defective glial cell morphology and a sensory defect in a subpopulation. A gain-of-function strategy in which mCARM1 was introduced in the morpholino-treated embryos exhibited recovery of the sensory defect phenotype. This study thus establishes the functional cooperation between arginine methylation and microRNA expression in the neuronal developmental process, with potential implications in sensory development pathways.
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India.
B Ruthrotha
BR
Selvi
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India.
Amrutha
A
Swaminathan
Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
Uma
U
Maheshwari
Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
Ananthamurthy
A
Nagabhushana
Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
Rakesh K
RK
Mishra
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India tapas@jncasr.ac.in.
Tapas K
TK
Kundu
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D058732:Embryoid Bodies / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000071317:Nanog Homeobox Protein; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D006657:Histones; D018398:Homeodomain Proteins; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1