Research Officer, Centenary Institute
In this project, I analyze mechanisms underlying a largely overlooked form of alternative splicing, intron retention (IR), with impact on gene regulation, cell physiology, and disease. IR is a widespread phenomenon in which the splicing machinery fails to excise introns from primary transcripts. This can lead to diverse downstream effects, such as the synthesis of novel peptides, RNA decay, or the suppression of protein or non-coding RNA synthesis. Recently, IR was described as a widespread mechanism of tumor suppressor inactivation, which suggests a significant contribution to cancer emergence and progression. I employ machine-learning approaches and pattern recognition algorithms to unravel the molecular causes for IR events and to determine the extent to which IR is conserved in other species. The integration and mining of massive amounts of RNA-sequencing and epigenomics data, including leukemia patient data, helps me to generate deeper insights into IR, its origins, mechanisms of regulation, and its role in cancer. There is evidence that IR can be used to enhance disease outcome predictions. Therefore, one of my aims is to derive an IR-based biomarker for leukemia. Understanding how IR events are triggered and suppressed will open the way for exploring novel avenues for cancer treatment. For this purpose, I am designing and implementing a cancer transcriptomics analysis pipeline to uncover alternative splicing events, including IR, that may lead to cancer pathogenesis and progression. Moreover, I'm developing an algorithm for the prediction of IR occurrences and possible pathogenic consequences. In summary, I'm actively involved in the advancements of our understanding of gene regulation, and implications for cancer pathogenesis. My ultimate goal is to develop patient-tailored therapeutic regimens with a particular emphasis on leukemia.
Abstract: RNA sequencing has revealed a striking diversity in transcriptomic complexity, to which alternative splicing is a major contributor. Intron retention (IR) is a conserved form of alternative splicing that was originally overlooked in normal mammalian physiology and development, due mostly to difficulties in its detection. IR has recently been revealed as an independent mechanism of controlling and enhancing the complexity of gene expression. IR facilitates rapid responses to biological stimuli, is involved in disease pathogenesis, and can generate novel protein isoforms. Many challenges, however, remain in detecting and quantifying retained introns and in determining their effects on cellular phenotype. In this review, we provide an overview of these challenges, and highlight approaches that can be used to address them.
Pub.: 26 Jul '17, Pinned: 30 Aug '17
Abstract: Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs. Our bioinformatic analyses of transcriptomic and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control. IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes. Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content. IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway. In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis. Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation.
Pub.: 06 Aug '13, Pinned: 30 Aug '17
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