Dynamics and Functional Roles of Splicing Factor Autoregulation

Ding, Fangyuan; Su, Christina; Chow, Ke-Huan K.; Liang, Guohao; Elowitz, Michael B.

doi:10.2139/ssrn.3892428

Cited by 4 publications

(6 citation statements)

References 62 publications

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“…Together, these results support the idea that alternative isoforms play a critical regulatory role that includes use of premature stop codons and complex alternative splicing in the 5’ UTR, gene body and 3’ UTRs. While these isoforms had been predicted by analysis of EST data and in cell culture, to our knowledge, direct evidence of regulated splicing patterns of any of these regulators in single cells has been missing (Ding et al 2022; Lareau et al 2007).…”

Section: Genes With Pan-tissue Single-cell-regulated Splicing Are Enr...mentioning

confidence: 95%

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

Dehghannasiri

Henderson

Bierman

et al. 2022

Preprint

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Myriad mechanisms diversify the sequence content of eukaryotic transcripts at the DNA and RNA level with profound functional consequences. Examples include diversity generated by RNA splicing and V(D)J recombination. Today, these and other events are detected with fragmented bioinformatic tools that require predefining a form of transcript diversification; moreover, they rely on alignment to a necessarily incomplete reference genome, filtering out unaligned sequences which can be among the most interesting. Each of these steps introduces blindspots for discovery. Here, we develop NOMAD+, a new analytic method that performs unified, reference-free statistical inference directly on raw sequencing reads, extending the core NOMAD algorithm to include a micro-assembly and interpretation framework. NOMAD+ discovers broad and new examples of transcript diversification in single cells, bypassing genome alignment and without requiring cell type metadata and impossible with current algorithms. In 10,326 primary human single cells in 19 tissues profiled with SmartSeq2, NOMAD+ discovers a set of splicing and histone regulators with highly conserved intronic regions that are themselves targets of complex splicing regulation and unreported transcript diversity in the heat shock protein HSP90AA1. NOMAD+ simultaneously discovers diversification in centromeric RNA expression, V(D)J recombination, RNA editing, and repeat expansions missed by or impossible to measure with existing bioinformatic methods. NOMAD+ is a unified, highly efficient algorithm enabling unbiased discovery of an unprecedented breadth of RNA regulation and diversification in single cells through a new paradigm to analyze the transcriptome.

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Section: Genes With Pan-tissue Single-cell-regulated Splicing Are Enr...mentioning

confidence: 95%

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

Dehghannasiri

Henderson

Bierman

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Most of the autoregulation mechanisms of splicing genes are reduced to feedback loops. This is due to the fact that RNAbinding proteins (RBPs) bind to and directly affect their own mRNAs, controlling their expression [148][149][150]. The question of the existence of positive feedback loops (feedforward loops) at the posttranscriptional level remains open.…”

Section: Autoregulation Of Splicing Factorsmentioning

confidence: 99%

“…Protein Mechanisms of autoregulation References SR proteins SRSF1 (ASF/SF2) alternative splicing associated with NMD or nuclear retention; protein overexpression reduces the translational efficiency of its own mRNA [150,180] SRSF2 (SC35) alternative splicing associated with NMD [181] SRSF3 (SRp20) alternative splicing associated with NMD; alternative splicing resulted in protein isoform with impaired function [182] SRSF4 (SRp75) alternative splicing associated with NMD (?) [183] SRSF5 (SRp40) alternative splicing associated with NMD [184,185] SRSF7 (9G8) alternative splicing associated with NMD or nuclear retention [156] SRSF10 alternative splicing resulted in protein isoform with impaired function [163] TRA2B alternative splicing associated with NMD [186] hnRNPs hnRNP A2B1 alternative splicing associated with NMD [187] hnRNP I (PTBP1) alternative splicing associated with NMD [188,189] hnRNP L alternative splicing associated with NMD [190] FUS/TLS alternative splicing resulted in protein isoforms with different cellular localization [191] hnRNP M alternative splicing associated with NMD (bioinformatic prediction) [155] TDP43 alternative splicing associated with NMD or nuclear retention and exosomemediated decay [161,192] Other Fox proteins (Fox-1, −2, −3) alternative splicing resulted in protein isoforms which antagonize Fox activity [157] MBNL1 alternative splicing associated with NMD; alternative splicing resulted in protein isoforms with different cellular localization [158,193] RBM10 alternative splicing associated with NMD [194] RBM39 alternative splicing associated with NMD (bioinformatic prediction) [155] SFPQ alternative splicing associated with NMD [155] TIA1 alternative splicing associated with NMD [195] U1A binding to and inhibiting the polyadenylation of its own pre-mRNA (through PAP inhibition)…”

Section: Protein Familymentioning

confidence: 99%

Non-canonical functions of spliceosome components in cancer progression

et al. 2023

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Dysregulation of pre-mRNA splicing is a common hallmark of cancer cells and it is associated with altered expression, localization, and mutations of the components of the splicing machinery. In the last few years, it has been elucidated that spliceosome components can also influence cellular processes in a splicing-independent manner. Here, we analyze open source data to understand the effect of the knockdown of splicing factors in human cells on the expression and splicing of genes relevant to cell proliferation, migration, cell cycle regulation, DNA repair, and cell death. We supplement this information with a comprehensive literature review of non-canonical functions of splicing factors linked to cancer progression. We also specifically discuss the involvement of splicing factors in intercellular communication and known autoregulatory mechanisms in restoring their levels in cells. Finally, we discuss strategies to target components of the spliceosome machinery that are promising for anticancer therapy. Altogether, this review greatly expands understanding of the role of spliceosome proteins in cancer progression.

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“…The naturally evolved transcriptional regulatory networks frequently utilize direct negative feedback regulation (or autorepression) for E. coli and the differentiation of mammalian cells. − Previous studies show that autorepression modules can linearize the switching performance of TFs, reduce intrinsic noises, and enhance the evolutionary stability of genetic systems. − In addition, recent studies show that autorepression of splicing factors plays a central role in homeostatically regulating transcriptional processes . However, direct negative feedback modules have not yet been utilized to alleviate unintended circuit–host interferences and maintain circuit performances; especially, the quantitative design principles of autorepression modules are not fully grasped, hindering its usage in predictable construction of host-adaptable regulatory systems.…”

Section: Introductionmentioning

confidence: 99%

“…35−38 regulating transcriptional processes. 39 However, direct negative feedback modules have not yet been utilized to alleviate unintended circuit−host interferences and maintain circuit performances; especially, the quantitative design principles of autorepression modules are not fully grasped, hindering its usage in predictable construction of host-adaptable regulatory systems.…”

Section: ■ Introductionmentioning

confidence: 99%

Mitigating Host Burden of Genetic Circuits by Engineering Autonegatively Regulated Parts and Improving Functional Prediction

et al. 2022

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Mitigating unintended interferences between circuits and host cells is key to realize applications of synthetic regulatory systems both for bacteria and mammalian cells. Here, we demonstrated that growth burden and circuit dysregulation occurred in a concentration-dependent manner for specific transcription factors (CymR*/CymR) in E.coli, and direct negative feedback modules were able to control the concentration of CymR*/CymR, mitigate growth burden, and restore circuit functions. A quantitative design scheme was developed for circuits embedded with autorepression modules. Four key parameters were theoretically identified to determine the performance of autoregulated switches and were experimentally modified by fine-tuning promoter architectures and cooperativity. Using this strategy, we synthesized a number of switches and demonstrated its improvement of product titers and host growth controlling the complex deoxyviolacein biosynthesis pathway. Furthermore, we restored functions of a dysregulated multilayer NOR gate by integrating autorepression modules. Our work provides a blueprint for engineering host-adaptable synthetic systems.

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Dynamics and Functional Roles of Splicing Factor Autoregulation

Cited by 4 publications

References 62 publications

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

Non-canonical functions of spliceosome components in cancer progression

Mitigating Host Burden of Genetic Circuits by Engineering Autonegatively Regulated Parts and Improving Functional Prediction

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