PB1424 - PCF11 is a central hub in the regulation of inflammation in an animal model of septicemia

Background: mRNA 3’ untranslated regions (3'UTRs) are dynamically regulated under immune and inflammatory conditions in several cell types. However, the effect on whole organisms of such coordinated processes remains enigmatic. Shortening of 3'UTRs is an evolutionary conserved feature that facilitates an effective and robust immune-inflammatory response, allowing the escape from repressing post-transcriptomic mechanisms including miRNAs. Among various mechanisms, PCF11 recently emerged as a master regulator of transcription termination globally affecting 3’UTR structures.

Aims: To evaluate whether the manipulation of the 3’UTR transcriptome architecture can dictate the outcome of inflammation and inflammation-associated cardiovascular perturbations.

Methods: A newly generated inducible PCF11 knock-down mouse model was challenged with 2 mg/kg LPS i.p. Monitoring of vascular flow was obtained through injection of fluorescent microbeads intravenously and analyzed in liver and lungs through an IVIS Imager. Cytokine and chemokine levels were evaluated analyzing animal sera with a multi-array assay. Transcriptome expression levels were analyzed on an Illumina HiSeq with 3’end sequencing.

Results: PCF11 depletion, promoting 3’UTR lengthening, results in the downregulation of inflammation, including a sepsis-related reduction of vascular flow in lungs and liver. Reduction of inflammation is also mirrored by a general downregulation of several cytokines and chemokines on a systemic level. Ultimately, 3’UTR sequencing of whole organs reveals lower expression of a broad range of inflammation-related transcripts.

Conclusion(s): We show here, for the first time, that PCF11, a global regulator affecting the 3’UTR transcriptome architecture, directs the inflammatory phenotype. PCF11 depletion dampens the inflammatory response in septicemia, while leaving the basal level of central inflammatory transcripts unaltered. PCF11 thus emerges as a promising novel target for management and treatment of various inflammatory conditions.