In silico analysis of alternative splicing on drug-target gene interactions

Abstract

full-length protein-coding transcripts, highlighting the complexity of the total proteome that can be expressed by different cells and tissues in the human body. Numerous studies have noted the functional importance of maintaining a coordinated regulation of alternative events in various biological processes, such as tissue development and aging 7-9. Isoforms of a gene often appear to have different, sometimes even opposite functions, and are tightly regulated to express in a context-specific manner. Conversely, a disruption of such coordinated regulation is often linked to diseases, such as cancer. A recent large transcriptome-wide study revealed that ~19% genes consistently undergo isoform switching (context-dependent differential usage of isoforms) that potentially have functional consequences across 12 solid cancer types 10. Such genes with isoform switching were previously found to relate to all hallmarks of cancer, in particular apoptosis and metastasis 11,12. One best example of such aberrant isoform switching in angiogenesis is VEGFA gene, where a switching from anti-angiogenic isoform VEGFA 165 b to pro-angiogenic splice variant VEGFA 165 is observed in multiple types of cancers 13-17. Another apoptosis-related example is the BCL2L1 gene, where a switching from pro-apoptotic short isoform Bcl-xs to anti-apoptotic long splice variant Bcl-xl enable cancer to bypass programmed cell death 18-20. Examples for metastasis-enabling isoform switching include cell surface adhesion receptors, such as CD44 21 and CDH1 (E-cadherin) 22 ; growth factor receptors, such as FGFR2 23 and TGFBR2 24 ; as well as other proteins that induce EMT and confer enhanced invasiveness/motility of cells, such as the Rac1b isoform of RAC1 gene 25-27 and a short-form, constitutively active isoform of RON gene (RonΔ165) 28. Importantly, the RON gene simultaneously produces other tumor-promoting or tumor-opposing isoforms involved in different pathways under different conditions 5. Meanwhile, the aberrant splicing of RAC1 gene has also been linked with multiple other cancer hallmarks, including proliferation, genome instability and inflammation 12. Another aberrant splicing example responsible for sustained proliferative signaling is BRAF gene, as alternative isoforms of wild-type and V600E mutant affect its kinase domain and may confer resistance to treatment 29,30. For isoforms related to evading growth suppressors, human TP53 itself serves as a perfect example, as many splice variants exists for this well-studied tumor suppressor, some of which are dominant-negative hampering anti-tumor function of wild-type p53 31,32. In addition, alternatively spliced, dominant negative isoforms of human telomerase gene TERT were identified in multiple cancers 33,34 , while splice variants for HLA-G protein were found on surface of tumor cells that enhance immune evasion 35. The above examples suggest that disease-causing splice variants, or aberrant isoforms, not only can function as important biomarkers but also have the potential of becoming succes...

Target isoforms are an overlooked challenge and opportunity in chimeric antigen receptor cell therapy

“…At least 75% of human protein-coding genes give rise to multiple distinct protein isoforms 2 , which can severely affect the sensitivity of therapeutic targeting of specific proteins. In a recent study of 883 small molecule cancer drugs targeting 1,434 different proteins, the authors found that 76% of these drugs would miss a target isoform if a switch occurred, or induce off-target effects in isoforms expressed in normal tissues 3 . Because isoforms of a protein may be differentially expressed in individual cancer cells 4 , they may produce a pool from which escape variants can arise when selective pressure is exerted by targeted therapy.…”

DNABERT: pre-trained Bidirectional Encoder Representations from Transformers model for DNA-language in genome

“…While the genetic code explaining how DNA is translated into proteins is universal, the regulatory code that determines when and how the genes are expressed varies across different celltypes and organisms (2). Same cis-regulatory elements (CREs) often have distinct functions and activities in different biological contexts, while widely spaced multiple CREs may cooperate, resulting in context-dependent use of alternative promoters with varied functional roles (3)(4)(5)(6). Such observations suggest existence of polysemy and distant semantic relationship within sequence codes, which are key properties of natural language.…”

Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity

“…We analyzed the structures of some of the transcripts and found that some contain targeting domains of the drugs, while many of them do not. Some studies have found that splicing-regulated protein isoforms are closely related to drug evaluation [ 28 , 29 ], but more functions of the transcripts remain to be further explored.…”