The Nuclear-Retained Noncoding RNA MALAT1 Regulates Alternative Splicing by Modulating SR Splicing Factor Phosphorylation

By Vidisha Tripathi, J. Ellis, Zhen Shen, David Y. Song, Qun Pan, A. Watt, Susan M. Freier, C. F. Bennett, Alok K. Sharma, Paula A Bubulya and 3 more. Molecules and Cells, 2010

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SUMMARY Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or cell-type-specific AS in a concentration- and phosphorylation-dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 or overexpression of an SR protein changes the AS of a similar set of endogenous pre-mRNAs. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight the role for an nrRNA in the regulation of gene expression.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6163d65ec6f4a983787748c9069e65e728542332

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Citations in the corpus

LncRNA: a link between RNA and cancer. (2014, background): “changes of the alternative splicing of a set of endogenous pre-mRNAs (Fig 1f) [26].”
Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA (2017, background): “In addition to the mechanisms described here, lncRNA has also been implicated in the regulation of mRNA splicing by modulating the levels of serine/arginine splicing factors within nuclear speckles [93].”
Linking Long Noncoding RNA Localization and Function. (2016, background): “MALAT1 localizes to nuclear speckles, which contain various splicing factors [28], and has been recently shown to regulate mammary cancer pathogenesis [29].”
Long Noncoding RNAs: Past, Present, and Future (2013, background): “MALAT1 is associated with proper relocation of these splicing factors to sites of transcription, where splicing occurs, and thus may have a role in controlling alternative splicing of certain mRNA precursors (Tripathi et al. 2010).”
LncRNA-mediated regulation of cell signaling in cancer (2017, background): “On the other hand, MALAT1 can regulate alternative splicing of many genes by interaction with the serine–arginine (SR) proteins and influencing their subnuclear localization (Tripathi et al 2010).”
TANRIC: An interactive open platform to explore the function of lncRNAs in cancer (2015, positive): “Emerging evidence has indicated that lncRNAs contribute to tumor initiation and progression through diverse mechanisms ranging from epigenetic regulation of key cancer genes (5, 6) and enhancer-associated activity (7) to posttranscriptional processing of mRNAs (8, 9).”
Characterising the RNA targets and position-dependent splicing regulation by TDP-43; implications for neurodegenerative diseases (2011, background): “and the MALAT1 ncRNA recruits splicing factors to nuclear speckles and affects phosphorylation of serine/arginine-rich splicing factor protein”
Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. (2012, background): “Other lncRNAs may act as decoys in the sequestration of miRNAs (Poliseno et al. 2010), transcription factors (Hung et al. 2011), or other proteins (Tripathi et al. 2010).”
Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs (2012, background): “The lncRNA MALAT1 (metastasisassociated lung adenocarcinoma transcript 1), which was initially identified in a screen for genes associated with metastasis, plays a critical role in pre-mRNA alternative splicing (68).”
A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA (2011, positive): “…Complex (PRC) was described for the Xist and HOTAIR transcripts (Chaumeil et al., 2006; Rinn et al., 2007). lncRNAs were also found to act in the nucleus as antisense transcripts or as decoy for splicing factors leading to splicing malfunctioning (Beltran et al., 2008; Tripathi et al., 2010).”
Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels (2019, background): “MALAT1 recruits SR proteins to the transcriptional active region, thereby regulating the variable cleavage of mRNA precursors (Figure 5B) [12].”
Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer (2016, background): “For example, MALAT1 controls alternative splicing by regulating the phosphorylation and distribution of serine/ arginine splicing factors in nuclear speckle domains [131].”