A Germ Cell-specific Gene, Prmt5, Works in Somatic Cell Reprogramming

Nagamatsu, Go; Kosaka, Takeo; Kawasumi, Miyuri; Kinoshita, Taisuke; Takubo, Keiyo; Akiyama, Hideo; Sudo, Tetsuo; Kobayashi, Takashi; Oya, Mototsugu; Suda, Toshio

doi:10.1074/jbc.m110.216390

Cited by 71 publications

(72 citation statements)

References 33 publications

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“…S1C; Supplemental Table S1). This stringently defined list concentrates factors that were previously identified as facilitators of reprogramming, such as Ezh2, Suz12, Wdr5, Sirt6, and Prmt5 (Ang et al 2011;Nagamatsu et al 2011;Onder et al 2012;Sharma et al 2013;Ding et al 2014), thus validating our screen. However, it also included many factors that have not been previously implicated in reprogramming.…”

Section: A Functional Rnai Screen For Epigenetic Regulators Of Reprogmentioning

confidence: 99%

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

et al. 2015

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Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we performed a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identified components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we showed in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that, upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed-forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming.

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Section: A Functional Rnai Screen For Epigenetic Regulators Of Reprogmentioning

confidence: 99%

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

et al. 2015

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“…Interestingly, PRMT5S enhanced the differentiation of dendritic cells whereas PRMT5L showed an inhibitory effect in ectopic expression assays (M. Sohail, S. Kung, and J. Xie, unpublished data). The different effects on cellular processes along with spatially and temporally regulated alternative splicing of the two variants thus likely contribute to the diverse roles of PRMT5, including but not limited to the maintenance of stem cell pluripotency and promotion of cancer cell growth as well as cell differentiation (34,(41)(42)(43)(44)(45)(46)62). Understanding these effects could be facilitated by revealing the potentially different profiles of methylation targets and enzyme activities of the PRMT5 isoforms in subcellular locations and compartments in future investigations.…”

Section: Discussionmentioning

confidence: 99%

“…It controls gene transcription/RNA processing (32,(38)(39)(40), maintains circadian rhythm and stem cell pluripotency or proliferation (34,(40)(41)(42)(43), accelerates cell cycle progression (44,45), and promotes tumorigenesis (37,46). However, the molecular basis of these diverse roles in cellular processes has not been fully understood.…”

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confidence: 99%

Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

Sohail

Xie

2015

Molecular and Cellular Biology

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Alternative splicing contributes greatly to the diversification of mammalian proteomes, but the molecular basis for the evolutionary emergence of splice variants remains poorly understood. We have recently found a novel class of splicing regulatory elements between the polypyrimidine tract (Py) and 3= AG (REPA) at intron ends in many human genes, including the multifunctional PRMT5 (for protein arginine methyltransferase 5) gene. The PRMT5 element is comprised of two G tracts that arise in most mammals and accompany significant exon skipping in human transcripts. The G tracts inhibit splicing by recruiting heterogeneous nuclear ribonucleoprotein (hnRNP) H and F (H/F) to reduce U2AF65 binding to the Py, causing exon skipping. The resulting novel shorter variant PRMT5S exhibits a histone H4R3 methylation effect similar to that seen with the original longer PRMT5L isoform but exhibits a distinct localization and preferential control of critical genes for cell cycle arrest at interphase in comparison to PRMT5L. This report thus provides a molecular mechanism for the evolutionary emergence of a novel splice variant with an opposite function in a fundamental cell process. The presence of REPA elements in a large group of genes implies their wider impact on different cellular processes for increased protein diversity in humans.A lternative precursor mRNA (pre-mRNA) splicing greatly increases the proteomic diversity in metazoans (1-3). In particular, splice variants have reached the highest complexity in humans and other primates (4, 5), with about 90% of human genes alternatively spliced (6, 7). Aberrant splicing causes a large fraction of human genetic diseases (8, 9). However, the molecular basis for the evolutionary emergence of alternative exons that impact protein functions and cellular processes remains largely unknown, although several models have been proposed (10).The 3= end of introns between the polypyrimidine tract (Py) and 3=AG is highly constrained in sequence and length, with a consensus sequence of PyNYAG (Y, pyrimidine; N, any nucleotide) (11). However, we have found a CA-rich splicing regulatory element called CaRRE1 at this location (12-15), suggesting relaxation of the constraint in some transcripts and the potential existence of other, similar elements. In particular, a purine-rich (Grich or A-rich) element such as a G tract at this location is expected to strongly disrupt the 3= splice site (3=SS).G tracts with a minimal functional GGG motif are splicing regulatory elements bound by heterogeneous nuclear ribonucleoprotein (hnRNP) H (H1) or its paralogues, including hnRNP F (16-24). They are enhancers or silencers of splicing, depending on their location in the pre-mRNA (17, 22, 24-28). We have identified G tracts between the Py and 3= AG in more than a thousand human genes, including PRMT5 (for protein arginine methyltransferase 5). We call elements at this location REPA (regulatory elements between the Py and 3=AG) (29). These REPA G tracts appear to have mostly emerged in mammalian ancestors to ...

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“…Although Blimp1 (Prdm1) is required for development of the posterior limb bud, the mutant phenotype is different from that of Prmt5 cKOs (Robertson et al, 2007), implying a different mechanism of regulation. In several stem cell populations, PRMT5 helps maintain pluripotency by inhibiting differentiation factors (Ancelin et al, 2006;Nagamatsu et al, 2011;Tee et al, 2010), suggesting that a similar mechanism could be regulating both stem cells and progenitor cells within the limb bud during development. Interestingly, an in vivo population of Grem1-expressing mesenchymal skeletal stem cells was recently identified that has the potential to give rise to bone and cartilage in postnatal animals (Worthley et al, 2015).…”

Section: Prmt5-mediated Mechanisms For Maintaining Progenitor Cellsmentioning

confidence: 99%

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

Norrie

et al. 2016

Development

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During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis.

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A Germ Cell-specific Gene, Prmt5, Works in Somatic Cell Reprogramming

Cited by 71 publications

References 33 publications

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

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