Appropriate expression of protein coding genes in mammalian cells requires complex nuclear choreography. Pre-mRNA processing complexes are recruited to transcription sites for capping, splicing and polyadenylation, yielding mature mRNA transcripts for nuclear export (Hirose and Manley, 2000; Lewis and Tollervey, 2000; Bentley 2005). While we understand some details about how RNA polymerase II (RNAPII) initiates transcription at promoters, or how snRNP complexes assemble into spliceosomes at splicing sites, there are gaps in our understanding about how spatiotemporal organization of gene expression within mammalian nuclei is coordinated. Nuclear speckles are domains in nuclei of higher eukaryotes enriched in pre-mRNA processing factors; dynamic exchange permits co-transcriptional pre-mRNA processing (Lamond and Spector, 2003). Our long-term goal is to understand assembly and function of nuclear speckle components and how this impacts pre-mRNA processing. Pinning down nuclear speckle functions has proven to be difficult because they contain at least 180 proteins and an undefined number of noncoding RNAs. Our lab showed that a protein called SON maintains proper organization of pre-mRNA processing factors in nuclear speckles (Sharma et al., 2010). A novel feature of SON is its unique tandem repeats that mediate proper nuclear speckle organization (Sharma et al., 2010). Two new pieces of evidence from our laboratory suggest that SON is also important for gene expression. First, SON is enriched at a facultative heterochromatin gene locus in its silent state, is removed during locus activation, and SON's repeats confer this function. Second, SON is required for appropriate alternative splicing of many gene transcripts. Our hypothesis is that SON influences gene expression via chromatin association as well as pre-mRNA splicing control for a defined subset of protein coding genes. This project aims to define SON-chromatin interactions and to design novel tools to investigate SON-dependent pre-mRNA splicing in situ.

Public Health Relevance

SON is an anti-apoptotic (Sun et al. 2001) mitotic spindle-associated (Nousiainen et al. 2006) protein that is required for cell growth/survival, cell cycle progression (Ahn et al., 2008; Sharma, et al., 2010; Huen et al., 2010) and nuclear speckle organization of pre-mRNA processing factors (Sharma et al, 2010). SON is a likely candidate for gene regulation in viral infection, as shown by its ability to repress the hepatitis B virus core promoter leading to reduced replication (Sun et al., 2001), and its ability to promote influenza virus trafficking and viral RNA production (Karlas et al., 2010). The implications for SON in transcription/splicing regulation, cell death response, developmental delay and intellectual disability underscores the public health relevance for understanding functions for SON in human development and human diseases such as HBV/influenza viral infection and cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Gaillard, Shawn R
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Wright State University
Schools of Arts and Sciences
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Varia, Sapna; Cheedu, Divya; Markey, Michael et al. (2017) Alignment of Mitotic Chromosomes in Human Cells Involves SR-Like Splicing Factors Btf and TRAP150. Int J Mol Sci 18:
Kim, Jung-Hyun; Shinde, Deepali N; Reijnders, Margot R F et al. (2016) De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet 99:711-719
Battini, Vishnu Priya; Bubulya, Athanasios; Bubulya, Paula A (2015) Accurate splicing of HDAC6 pre-mRNA requires SON. Int J Mol Sci 16:5886-99
Lu, Xinyi; Ng, Huck-Hui; Bubulya, Paula A (2014) The role of SON in splicing, development, and disease. Wiley Interdiscip Rev RNA 5:637-46
Lu, Xinyi; Göke, Jonathan; Sachs, Friedrich et al. (2013) SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells. Nat Cell Biol 15:1141-1152
Varia, Sapna; Potabathula, Divya; Deng, Zhihui et al. (2013) Btf and TRAP150 have distinct roles in regulating subcellular mRNA distribution. Nucleus 4:229-40
Peng, Hong-Juan; Henkels, Karen M; Mahankali, Madhu et al. (2011) The dual effect of Rac2 on phospholipase D2 regulation that explains both the onset and termination of chemotaxis. Mol Cell Biol 31:2227-40
Sharma, Alok; Markey, Michael; Torres-Munoz, Keshia et al. (2011) Son maintains accurate splicing for a subset of human pre-mRNAs. J Cell Sci 124:4286-98
Sharma, Alok; Takata, Hideaki; Shibahara, Kei-ichi et al. (2010) Son is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell 21:650-63
Tripathi, Vidisha; Ellis, Jonathan D; Shen, Zhen et al. (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925-38

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