RNA splicing control

Abstract

The mammalian genome harbors a large number of long non-coding RNAs (lncRNAs) that do not code for proteins, but rather they exert their function directly as RNA molecules. LncRNAs are involved in executing several vital cellular functions. They facilitate the recruitment of proteins to specific chromatin sites, ultimately regulating processes like dosage compensation and genome imprinting. LncRNAs are also known to regulate nucleocytoplasmic transport of macromolecules. A large number of the regulatory lncRNAs are retained within the cell nucleus and constitute a subclass termed nuclear-retained RNAs (nrRNAs). NrRNAs are speculated to be involved in crucial gene regulatory networks, acting as structural scaffolds of subnuclear domains. NrRNAs modulate gene expression by influencing chromatin modification, transcription and post-transcriptional gene processing. The cancer-associated Metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is one such long nrRNA that regulates pre-mRNA processing in mammalian cells. Thus far, our understanding about the roles played by nrRNAs and their relevance in disease pathways is only ‘a tip of an iceberg’. It will therefore be crucial to unravel the functions for the vast number of long nrRNAs, buried within the complex mine of the human genome.

Acknowledgments

We thank the members of Prasanth lab for discussion. We also would like to thank Drs. Paula Bubulya and Supriya Prasanth for critical reading of the manuscript and for providing valuable suggestions. This work was supported by the University of Illinois start-up funds and American Cancer Society, Research Scholar grant (RSG-11-174-01-RMC) to K.V.P.

Figures and Tables

Figure 1 (A) Co-RNA-FISH using probes against MALAT1 (a, green) and Neat1 (a′, red) reveals distribution of MALAT1 and Neat1 RNA in nuclear speckles and paraspeckles respectively. (B) Depletion of MALAT1 (MALAT1-AS) in HeLa cells results in nuclear fragmentation. Note that the fragmented nuclei contain nuclear pores (green) and nuclear lamina (red). DNA is counterstained with DAPI. The bar represents 5 µm.

Figure 2 Model depicting the biogenesis of MALAT1 and the involvement of MALAT1 in alternative splicing regulation. (A) By associating with splicing factors in nuclear speckles and the nucleoplasm, MALAT1 regulates the nuclear distribution and recruitment of splicing factors to pre-mRNA, thereby modulating alternative splicing. the color boxes indicate exons and the lines indicate introns. (B) the nascent MALAT1 transcript is cleaved at its 3′end to generate a mature long MALAT1 nuclear RNA and a small ∼61 nucleotide tRNA-like mascRNA, which is transported into the cytoplasm.147 ‘?’ indicates lack of clear evidence on whether nuclear speckles contain both the precursor and mature long MALAT1 transcripts or only the mature transcript.