Transcription Factor Positive Regulatory Domain 4 (PRDM4) Recruits Protein Arginine Methyltransferase 5 (PRMT5) to Mediate Histone Arginine Methylation and Control Neural Stem Cell Proliferation and Differentiation

Chittka, Alexandra; Nitarska, Justyna; Grazini, Ursula; Richardson, William D.

doi:10.1074/jbc.m112.392746

Cited by 89 publications

(81 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Its role in preserving the less-differentiated cellular state has been demonstrated in primordial germ cells, erythrocyte progenitors, embryonic stem cells, and neural stem cells [18, 20, 31, 32]. At the molecular level, symmetric dimethylation of arginine R3 on histones by PRMT5 is associated with transcriptional repression of genes involved in neural stem cell differentiation and neuronal lineage determination [33].…”

Section: Discussionmentioning

confidence: 99%

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Han

Zhang

et al. 2014

J Neurooncol

View full text Add to dashboard Cite

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Han

Zhang

et al. 2014

J Neurooncol

View full text Add to dashboard Cite

show abstract

“…In addition to histones, PRMT5 regulates a number of nonhistone proteins with identifiable functions in RNA processing, translation, signal transduction, apoptosis, and cell cycle regulation. PRMT5 has been shown to maintain pluripotency in both embryonic and adult stem cells and to reprogram mouse embryonic fibroblasts into induced pluripotent stem cells (iPSCs) when introduced with Klf4 and Oct3/4 (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

Liu¹,

Cheng

Hamard

et al. 2015

Journal of Clinical Investigation

132

152

View full text Add to dashboard Cite

R e s e a R c h a R t i c l e3 5 3 3 jci.orgVolume 125 Number 9 September 2015 levels decreased dramatically, suggesting important posttranscriptional regulation of PRMT5 expression in these cells. Since straight Prmt5-KO mice die before birth (12), we generated Prmt5-conditional KO mice by first crossing Prmt5 FLIP-OUT mice (obtained from the European Mutant Mouse Archive [EMMA]) with Flp recombinase-expressing transgenic (Tg) mice to generate Prmt5-floxed mice, whereby exon 7 of the Prmt5 time PCR (qPCR) ( Figure 1A) and Western blot analysis ( Figure 1B). Prmt5 mRNA and protein levels were readily detected in HSPCs, with little change in mRNA levels in the various stem and progenitor cell populations. However, when cells underwent myeloid, erythroid, or lymphoid differentiation, PRMT5 protein levels decreased to 5% to 24% of the levels seen in HSPCs. Although Prmt5 mRNA was maintained in differentiated B cells, its protein BM cells and found a complete loss of this modification 7 days after Cre induction ( Figure 1C), suggesting that PRMT5 is indeed the major type 2 PRMT in these cells. Deletion of PRMT5 during adult hematopoiesis leads to severe cytopenias. The deletion of PRMT5 in 2-month-old mice had a profound effect on hematopoiesis. Two weeks after the first poly(I:C) injection, the Mx1Cre + Prmt5 fl/fl mice developed severe pallor due to anemia, and most of these PRMT5-deleted mice were moribund 1 to 2 days later, requiring euthanasia. Analysis of the peripheral blood of these mice revealed severe pancytopenia, with a more than 10-fold decrease in wbc, a 5-fold decrease in rbc, and a 100-fold decrease in platelet counts 15 days after Cre induction ( Figure 1D). BM cellularity of the PRMT5-deleted mice was reduced by more than 50% on day 7 and by more than 95% on day 15 ( Figure 1E), consistent with the development of aplastic anemia ( Figure 1G). While PRMT5 loss had little effect on spleen weight (or cellularity) on day 15 (Supplemental Figure 2, A and B), the size and cellularity of the thymus were significantly reduced on day 15 gene was flanked by 2 LoxP sites (Supplemental Figure 1A; mice and Mx1Cre-negative littermate controls. To delete Prmt5 in hematopoietic cells, 2 i.p. injections of poly(I:C) (10 mg/kg on days 0 and 1) were given to both the Mx1Cre -and Mx1Cre + Prmt5-floxed mice. Prmt5 loss was confirmed by PCR analysis of genomic DNA (Supplemental Figure 1B), by quantitative qPCR to detect Prmt5 mRNA (Supplemental Figure 1C), and by Western blot analysis to detect PRMT5 protein (Supplemental Figure 1D). This injection strategy was used in all subsequent experiments. Interestingly, loss of PRMT5 triggered the loss of MEP50 protein (Supplemental Figure 1D), a cofactor that is required for the enzymatic activity of PRMT5 on histones, without changing Mep50 mRNA levels (data not shown). This suggests a probable posttranscriptional effect of PRMT5 on MEP50 protein levels. We also determined the overall level of symmetrically dimethylated arginine in PRMT5-deleted and Prmt5 Δ/Δ mice (n = 3). P...

show abstract

“…In recent years, the study of histone arginine methylation has attracted great attention. Studies have revealed a critical role for this mechanism in epigenetically controlled cellular processes (30) and the functional significance of specific histone methylation (20)(21)(22)(23)31). WDR77 is required for substrate specificity (32), and may define PRMT5-dependent histone methylation targets (22,33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Great attention has been paid to PRMT5-mediated methylation of specific arginine residues in histones. These modifications alter chromatin structure by affecting the recruitment of nonhistone proteins that modulate the accessibility of genomic DNA, thus tuning gene expression involved in cell-cycle progression, differentiation, and DNA repair, among other cellular functions (20)(21)(22)(23). As we recently demonstrated, the highly homologous M7CK phosphorylates specific histone S/T residues, enhancing neighboring lysine acetylation to alter gene expression (9).…”

Section: M6ck Phosphorylates Specific S/t Residues Of Histones and Atmentioning

confidence: 99%

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Krapivinsky

Renthal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating histone arginine residues. Histone phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in histone S/T phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific histone phosphorylation. M6CK histone phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.A mong the several hundred genes encoding cation channels, the melastatin-related transient receptor potential family members TRPM6 and TRPM7 are unique in also being serine/ threonine (S/T) kinases (1). The TRPM6 channel kinase was brought to greater attention when mutations in this chanzyme were found to be the cause of familial hypomagnesemia with secondary hypocalcemia (HSH; see ref. 2 for a recent review). Characterized by severe hypomagnesemia, infants with HSH suffer tetany and refractory seizures shortly after birth, resulting in permanent neurological damage or death if untreated. The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3-5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6, 7). Mice with loss of TRPM6 at intermediate developmental time points manifest a reduced life span and skeletal deformations, in addition to mild hypomagnesemia (5). These data indicate that, much like TRPM7 (8), TRPM6 may be critical for normal, developmental, tissue-specific regulation of gene activity.Recently, our laboratory uncovered a signaling pathway mediated by TRPM7, a channel sharing 52% homology with TRPM6, whereby the functional S/T kinase at the carboxyl terminus of TRPM7 is proteolytically cleaved from the channel domain, forming cleaved kinase fragments (M7CKs) that translocate to the nucleus (9). There, M7CKs bind components of chromatin-remodeling complexes to ultimately phosphorylate specific S/T residues of histones, regulate selected histone acetylatio...

show abstract

Transcription Factor Positive Regulatory Domain 4 (PRDM4) Recruits Protein Arginine Methyltransferase 5 (PRMT5) to Mediate Histone Arginine Methylation and Control Neural Stem Cell Proliferation and Differentiation

Cited by 89 publications

References 49 publications

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Contact Info

Product

Resources

About