PRMT1 and PRMT8 regulate retinoic acid-dependent neuronal differentiation with implications to neuropathology.
Retinoids are morphogens and have been implicated in cell fate commitment of embryonic stem cells (ESCs) to neurons. Their effects are mediated by RAR and RXR nuclear receptors. However, transcriptional cofactors required for cell and gene-specific retinoid signaling are not known. Here we show that protein arginine methyl transferase (PRMT) 1 and 8 have key roles in determining retinoid regulated gene expression and cellular specification in a multistage neuronal differentiation model of murine ESCs. PRMT1 acts as a selective modulator, providing the cells with a mechanism to reduce the potency of retinoid signals on regulatory "hotspots." PRMT8 is a retinoid receptor target gene itself and acts as a cell type specific transcriptional coactivator of retinoid signaling at later stages of differentiation. Lack of either of them leads to reduced nuclear arginine methylation, dysregulated neuronal gene expression, and altered neuronal activity. Importantly, depletion of PRMT8 results in altered expression of a distinct set of genes, including markers of gliomagenesis. PRMT8 is almost entirely absent in human glioblastoma tissues. We propose that PRMT1 and PRMT8 serve as a rheostat of retinoid signaling to determine neuronal cell specification in a context-dependent manner and might also be relevant in the development of human brain malignancy.
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
Zoltan
Z
Simandi
Erik
E
Czipa
Attila
A
Horvath
Aron
A
Koszeghy
Csilla
C
Bordas
Szilárd
S
Póliska
István
I
Juhász
László
L
Imre
Gábor
G
Szabó
Balazs
B
Dezso
Endre
E
Barta
Sascha
S
Sauer
Katalin
K
Karolyi
Ilona
I
Kovacs
Gábor
G
Hutóczki
László
L
Bognár
Álmos
Á
Klekner
Peter
P
Szucs
Bálint L
BL
Bálint
Laszlo
L
Nagy
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D005909:Glioblastoma; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D008565:Membrane Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C099988:PRMT1 protein, human; C505447:PRMT8 protein, human; C546992:PRMT8 protein, mouse; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
Glioblastoma; Neural differentiation; PRMT1; PRMT8; Retinoid signaling