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Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages

Jiang, Shuai and Yan, Wei and Wang, Shizhen Emily and Baltimore, David (2019) Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages. Proceedings of the National Academy of Sciences of the United States of America, 116 (25). pp. 12416-12421. ISSN 0027-8424. PMCID PMC7056939. https://resolver.caltech.edu/CaltechAUTHORS:20190603-141218777

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Abstract

Tet methylcytosine dioxygenase 2 (Tet2) is an epigenetic regulator that removes methyl groups from deoxycytosine residues in DNA. Tet2-deficient murine macrophages show increased lipopolysaccharide (LPS)-induced and spontaneous inflammation at least partially because Tet2 acts to restrain interleukin (IL)-1β and IL-6 expression in induced cells. MicroRNAs have emerged as critical regulatory noncoding RNAs that tune immune cell responses to physiological perturbations and play roles in pathological conditions in macrophages. To determine if a microRNA played any role in Tet2 activity, we examined the interrelationship of Tet2 action and the let-7 microRNA family, utilizing several let-7 microRNA engineered murine models. We first showed that Tet2, but not Tet3, is a direct target of the let-7a-1/let-7d/let-7f-1 (let-7adf) microRNAs in macrophages. We found that overexpression or deletion of the let-7adf gene cluster causes altered IL-6 induction both in tissue culture cells induced by LPS treatment in vitro as well as in a Salmonella infection mouse model in vivo. Mechanistically, let-7adf promotes IL-6 by directly repressing Tet2 levels and indirectly by enhancing a Tet2 suppressor, the key TCA cycle metabolite, succinate. We found that Let-7adf promotes succinate accumulation by regulating the Lin28a/Sdha axis. We thereby identify two pathways of let-7 control of Tet2 and, in turn, of the key inflammatory cytokine, IL-6, thus characterizing a regulatory pathway in which a microRNA acts as a feedback inhibitor of inflammatory processes.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1811040116DOIArticle
https://www.pnas.org/content/suppl/2019/05/31/1811040116.DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7056939/PubMed CentralArticle
ORCID:
AuthorORCID
Yan, Wei0000-0001-9519-1812
Wang, Shizhen Emily0000-0002-5036-8175
Baltimore, David0000-0001-8723-8190
Additional Information:© 2019 National Academy of Sciences. Published under the PNAS license. Contributed by David Baltimore, May 9, 2019 (sent for review June 27, 2018; reviewed by Xuetao Cao and Luke A. J. O’Neill). PNAS first published June 3, 2019. We thank Drs. George Daley (Harvard Medical School) and Antony Rodriguez for providing let-7adf KO mice. The let-7adf cluster iTg mice were a gift from Dr. Eric Olson (University of Texas Southwestern Medical Center), and the Lin28a iTg mice were a gift from Dr. Tatsuya Kobayashi (Massachusetts General Hospital). This study is supported by NIH Grants RO1AI079243 (to D.B.), R01CA218140 (to S.E.W.), and R01CA206911 (to S.E.W.). Author contributions: S.J. and D.B. designed research; S.J. and W.Y. performed research; S.J. and W.Y. analyzed data; and S.J., S.E.W., and D.B. wrote the paper. Reviewers: X.C., Peking Union Medical College, Chinese Academy of Medical Sciences; and L.A.J.O., Trinity College, Dublin. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1811040116/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHRO1AI079243
NIHR01CA218140
NIHR01CA206911
Subject Keywords:Tet2; lipopolysaccharide; Let-7; succinate; IL-6
Issue or Number:25
PubMed Central ID:PMC7056939
Record Number:CaltechAUTHORS:20190603-141218777
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190603-141218777
Official Citation:Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages. Shuai Jiang, Wei Yan, Shizhen Emily Wang, David Baltimore. Proceedings of the National Academy of Sciences Jun 2019, 116 (25) 12416-12421; DOI: 10.1073/pnas.1811040116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96045
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Jun 2019 21:22
Last Modified:03 Apr 2020 23:52

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