Intron retention (IR) is a mode of alternative splicing that occurs when an intron is not excised by the spliceosome, and is preserved in the final mature mRNA. Unlike many other alternative splicing events that promote protein diversity, IR is a distinctive mechanism that regulates genes expression via cytoplasmic nonsense-mediated decay or nuclear-enriched degradation mechanism(s). Herein, I will describe the discovery of IR as a widespread mechanism that controls the expression of functionally-related genes during haemapoietic cell differentiation. I will summarise my previous findings in granulocytes (1), erythroblasts and megakaryocytes, and new finding in monocytes and macrophages. I will present recent findings that IR is regulated by epigenetic changes. In particular, I will highlight my own work that IR is facilitated by reduced recruitment of splicing factors via decreased DNA methylation levels near splice junctions (2). I will also present data concerning the conservation of IR over 430 years of evolution in vertebrates (3). Finally, I will discuss the roles of IR in human cancers including its potential functions in regulating the expression of tumour suppressor genes and oncogenes.
1. Wong JJL*, Ritchie W*, Ebner O, Selbach M, Wong JWH, Huang Y, Gao D, Pinello N, Gonzalez M, Baidya K, Thoeng A, Khoo T-L, Bailey CG, Holst J & Rasko JEJ. (2013) Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154:583-595.(*Equal first)
2. Wong JJL*#, Gao D*, Nguyen TV*, Kwok C-T, van Geldermalsen M, Middleton R, Pinello N, Thoeng A, Nagarajah R, Holst J, Ritchie W#, Rasko JEJ#. (2017) Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment. Nat Commun. 8:15134.(*Equal first # co-corresponding)
3. Schmitz U, Pinello N, Jia F, Alasmari S, Ritchie W, Keightley MC, Shini S, Lieschke G, Wong JJL†, Rasko JEJ†. (2017) Intron retention enhances gene regulatory complexity in vertebrates. Genome Biol. 18:216.(†Equal last)