Elise Clayer, Inflammation division

Elise Clayer, Inflammation division

Location: 
Online
Start Time: 
Wed, 17/02/2021 - 1:00pm
End Time: 
Wed, 17/02/2021 - 2:00pm

WEHI Wednesday Seminar hosted by Dr Philippe Bouillet

Elise Clayer
PhD Student, Bouillet Laboratory, Inflammation division, Infection, Inflammation and Immunity Theme

The role of ZC3H12C in the post-transcriptional regulation of Tnf

 

This is a PhD completion seminar.

Join via TEAMS

Includes Q&A session

 

Tumour Necrosis Factor (TNF) is one of the most potent pro-inflammatory cytokines secreted in response to a danger signal. High levels of TNF have been associated with chronic and inflammatory diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis. To prevent high TNF levels and uncontrolled inflammation, Tnf mRNA is degraded when not required, through post-transcriptional regulation involving a cooperation between cis-elements present in the 3’UTR and trans-acting proteins such as RNA-binding proteins (RBPs). Understanding the precise and complete Tnf post-transcriptional regulation mechanism could be used as a therapeutic strategy to manipulate Tnf expression precisely.

We, and others, have previously identified three regulatory regions within Tnf 3’UTR. In my work, I have translated those findings in vivo, using the CRISPR/Cas9 technology to generate mice with deletions of one or two regulatory elements in Tnf 3’UTR. I showed that the variety of phenotypes changed considerably in severity and found that excessive TNF may lead to embryonic death. These observations suggested that cis-elements cooperate to destabilise Tnf mRNA efficiently, which appears to be a cell and tissue-specific mechanism. I further investigated the role of an RBP called ZC3H12C, which we previously identified in a screen to find new regulators of Tnf 3’UTR stability. I generated a mouse deficient in Zc3h12c to study the physiological role of protein, particularly in the context of TNF-dependent inflammation. I thoroughly defined the expression profile of the protein. I found that mice deficient in ZC3H12C developed lymphadenopathy of the skin-draining lymph nodes as they aged, associated to higher serum levels of IFNg and TNF, and was rescued upon concomitant loss of Tnf. Unexpectedly, 30% of Tnf/12c double knock-out mice developed lethal multiorgan auto-inflammation, including symptoms occasionally developed by patients receiving anti-TNF therapies. Therefore, Zc3h12c may be a risk factor in the context of anti-TNF treatments leading to autoimmunity in some patients.