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Programmed Delayed Splicing: A Mechanism for Timed Inflammatory Gene Expression

Majumdar, Devdoot S. and Frankiw, Luke and Burns, Christian H. and Garcia-Flores, Yvette and Baltimore, David (2018) Programmed Delayed Splicing: A Mechanism for Timed Inflammatory Gene Expression. . (Unpublished)

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Inflammation involves timed gene expression, suggesting that the fine-tuned onset, amplitude, and termination of expression of hundreds of genes is of critical importance to organismal homeostasis. Recent study of post-transcriptional regulation of inflammatory gene expression led to the suggestion of a regulatory role for pre-mRNA splicing. Here, using a hybrid capture approach to purify incompletely spliced, chromatin-associated pre-mRNAs, we use deep sequencing to study pre-mRNA splicing of the NF-kB transcriptome. By freezing transcription and examining subsequent splicing of complete transcripts, we find many introns splice tens to hundreds of times slower than average. In many cases, this is attributable to poor splice donor sequences that are evolutionarily conserved. When these introns were altered by ~2 base pairs to yield stronger splice donors, gene expression levels increased markedly for several genes in the context of a reporter system. We propose that such splice sites represent a regulatory mechanism that determines the timing of production of the mRNAs from certain inflammatory genes and may also limit mRNA expression from these genes. Further work will be needed to understand the roles of this regulation in the inflammatory response. The suggestion of extensive temporal regulation of pre-mRNA splicing as a regulatory process in inflammation raises the question of where else in biology there may be timed processes with a similar underlying cause.

Item Type:Report or Paper (Discussion Paper)
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URLURL TypeDescription Paper
Baltimore, David0000-0001-8723-8190
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv preprint first posted online Oct. 15, 2018. The authors would like to thank Alex Shishkin and Mitchell Guttman (Dept. of Biology, Caltech) for assistance with hybrid capture strategy design; and Ann-Jay Tong Stephen Smale, Doug Black and Amy-Pandya Jones (Dept. of Biology, University of California, Los Angeles) for insights and advice; and Sergei Manakov, Evelyn Stuwe, Dubravka Pezic, Igor Antoshechkin, Sagar Damle, and Alok Joglekar (Dept. of Biology, California Institute of Technology) for experimental and computational assistance. This work was funded from a grant from NIH and from an endowment provided by the Raymond and Beverly Sackler Foundation. Author Contributions: DSM/LF/CB/DB designed the experiments and wrote the manuscript. DSM/LF/CB/YG designed and conducted experiments, and DSM/LF performed bioinformatics analysis on the data.
Funding AgencyGrant Number
Raymond and Beverly Sackler FoundationUNSPECIFIED
Subject Keywords:inflammation, innate immunity, macrophage, gene expression, splicing
Record Number:CaltechAUTHORS:20181030-074928774
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Official Citation:Programmed Delayed Splicing: A Mechanism for Timed Inflammatory Gene Expression. Devdoot Majumdar, Luke Frankiw, Christian H. Burns, Yvette Garcia-Flores, David Baltimore. bioRxiv 443796; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90485
Deposited By: Tony Diaz
Deposited On:30 Oct 2018 17:13
Last Modified:16 Nov 2021 03:33

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