SAM68 interaction with U1A modulates U1 snRNP recruitment and regulates mTor pre-mRNA splicing

Subramania, Suryasree; Gagné, Laurence M.; Campagne, Sébastien; Fort, Victoire; O’Sullivan, Julia; Mocaer, Karel; Feldmüller, Miki; Masson, Jean‐Yves; Allain, Frédéric H.‐T.; Hussein, Samer M.I.; Huot, Marc‐Étienne

doi:10.1093/nar/gkz099

Cited by 20 publications

(24 citation statements)

References 71 publications

(107 reference statements)

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“…This study focused on the neuronal isoform selection in 3′ UTR by SAM68 and demonstrated their functional aspects through the identification of a novel target IL1RAP in neurons (Figure 5). Very recently, two articles also elucidated the interaction between SAM68 and U1 small nuclear ribonucleoprotein particle (snRNP) as a global mechanism underlying ALE regulation by SAM68 (Naro et al., 2019, Subramania et al., 2019), supporting our findings in the CNS. U1 snRNP prevents premature transcript termination by inhibition of cryptic PASs (Berg et al., 2012, Kaida et al., 2010).…”

Section: Discussionsupporting

confidence: 85%

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3′ UTR Isoforms in the Nervous System

et al. 2019

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Neuronal alternative splicing is a core mechanism for functional diversification. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs by STARs remains unclear. Here, we performed a transcriptomic analysis using SAM68 knockout and SAM68/SLM1 double-knockout midbrains. We revealed different alternative splicing activity between SAM68 and SLM1; SAM68 preferentially targets alternative 3 0 UTR exons. SAM68 knockout causes a long-to-short isoform switch of a number of neuronal targets through the alteration in alternative last exon (ALE) selection or alternative polyadenylation. The altered ALE usage of a novel target, interleukin 1 receptor accessory protein (Il1rap), results in remarkable conversion from a membrane-bound type to a secreted type in Sam68 KO brains. Proper ALE selection is necessary for IL1RAP neuronal function. Thus the SAM68-specific splicing program provides a mechanism for neuronal selection of alternative 3 0 UTR isoforms.

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Section: Discussionsupporting

confidence: 85%

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3′ UTR Isoforms in the Nervous System

et al. 2019

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“…Sam68 promotes exon 2 inclusion ( Fig. 2d, e) and it cooperates with the spliceosomal U1snRNP in exon recognition 28,22 . Analysis of testes from juvenile Sam68 knockout mice (P10) showed a significant reduction in Spo11 exon 2 inclusion (Fig.…”

Section: A Reduced Rnapii Elongation Rate Promotes Splicing Of Spo11αmentioning

confidence: 94%

“…RNAPII processivity within the transcription unit can also influence AS regulation [7][8][9]22 . Since RNAPII activity is modulated during male meiosis 12,23 , we asked whether Spo11 splicing is sensitive to changes in the RNAPII elongation rate.…”

Section: A Reduced Rnapii Elongation Rate Promotes Splicing Of Spo11αmentioning

confidence: 99%

Combinatorial control of Spo11 alternative splicing by modulation of RNA polymerase II dynamics and splicing factor recruitment during meiosis

et al. 2020

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Homologous recombination and chromosome segregation in meiosis rely on the timely expression of two splice variants of the endonuclease SPO11, named α and β, which respectively skip or include exon 2. However, in spite of its physiological importance, the mechanism underlying Spo11 alternative splicing in meiosis is still unknown. By screening the activity of factors that are predicted to bind the alternatively spliced region of Spo11, we identified hnRNPH as a key regulator of SPO11α splicing in mouse spermatocytes. Although hnRNPH was not upregulated in meiosis concomitantly with the switch in splicing, its recruitment to Spo11 pre-mRNA was favored by selective modulation of RNA polymerase II (RNAPII) phosphorylation and processivity in proximity of exon 2. The hnRNPH binding sites were localized near those of splicing factors that promote SPO11β splicing, suggesting that hnRNPH favors exon 2 skipping by competing out positive regulators. Indeed, hnRNPH binds proximal to a consensus motif for Sam68, a positive regulator of SPO11β splicing in vitro and in vivo, and it interferes with Sam68 binding to the Spo11 pre-mRNA. Thus, our work reveals that modulation of RNAPII dynamics in concert with hnRNPH recruitment exerts a combinatorial control of the timely regulated Spo11 splicing during meiosis.

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“…The functional AS outcomes of different splicing regulators have been convincingly documented in WAT adipogenesis. Sam68, highly involved in cellular RNA processing events and signal transduction pathways [ 70 , 89 ], has been demonstrated in adipocyte development to increase the number of early adipocyte progenitors by controlling AS of the mechanistic target of mTOR signaling [ 66 , 68 ]. The Sam68 binding sites often localize near AS junctions within pre-mRNAs, so they often engage in regulating neighboring alternative exon usage and splice site selection as either splicing enhancers or silencers [ 69 ].…”

Section: Introductionmentioning

confidence: 99%

Regulatory roles and mechanisms of alternative RNA splicing in adipogenesis and human metabolic health

et al. 2021

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Alternative splicing (AS) regulates gene expression patterns at the post-transcriptional level and generates a striking expansion of coding capacities of genomes and cellular protein diversity. RNA splicing could undergo modulation and close interaction with genetic and epigenetic machinery. Notably, during the adipogenesis processes of white, brown and beige adipocytes, AS tightly interplays with the differentiation gene program networks. Here, we integrate the available findings on specific splicing events and distinct functions of different splicing regulators as examples to highlight the directive biological contribution of AS mechanism in adipogenesis and adipocyte biology. Furthermore, accumulating evidence has suggested that mutations and/or altered expression in splicing regulators and aberrant splicing alterations in the obesity-associated genes are often linked to humans’ diet-induced obesity and metabolic dysregulation phenotypes. Therefore, significant attempts have been finally made to overview novel detailed discussion on the prospects of splicing machinery with obesity and metabolic disorders to supply featured potential management mechanisms in clinical applicability for obesity treatment strategies.

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SAM68 interaction with U1A modulates U1 snRNP recruitment and regulates mTor pre-mRNA splicing

Cited by 20 publications

References 71 publications

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3′ UTR Isoforms in the Nervous System

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3′ UTR Isoforms in the Nervous System

Combinatorial control of Spo11 alternative splicing by modulation of RNA polymerase II dynamics and splicing factor recruitment during meiosis

Regulatory roles and mechanisms of alternative RNA splicing in adipogenesis and human metabolic health

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