Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer?

Baptiste Dumetier; Camille Sauter; Azadeh Hajmirza; Baptiste Pernon; Romain Aucagne; Cyril Fournier; Céline Row; Fabien Guidez; Cédric Rossi; Côme Lepage; Laurent Delva; Mary B Callanan

doi:10.3390/biomedicines10123101

Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer?

Biomedicines. 2022 Dec 1;10(12):3101. doi: 10.3390/biomedicines10123101.

Authors

Baptiste Dumetier¹, Camille Sauter¹, Azadeh Hajmirza², Baptiste Pernon¹, Romain Aucagne^{1

3

4}, Cyril Fournier^{1

3}, Céline Row^{1

3}, Fabien Guidez¹, Cédric Rossi⁵, Côme Lepage¹, Laurent Delva¹, Mary B Callanan^{1

3

4}

Affiliations

¹ Faculty of Medicine, INSERM1231, University of Burgundy, 21000 Dijon, France.
² Institute for Research in Immunology and Cancer, Montreal, QC H3C 3J7, Canada.
³ Unit for Innovation in Genetics and Epigenetics in Oncology, Dijon University Hospital, 21000 Dijon, France.
⁴ CRIGEN, Crispr-Functional Genomics, Dijon University Hospital and University of Burgundy, 21000 Dijon, France.
⁵ School of Medicine, Stanford University, Stanford, CA 94305, USA.

Abstract

The human genome is composed of unique DNA sequences that encode proteins and unique sequence noncoding RNAs that are essential for normal development and cellular differentiation. The human genome also contains over 50% of genome sequences that are repeat in nature (tandem and interspersed repeats) that are now known to contribute dynamically to genetic diversity in populations, to be transcriptionally active under certain physiological conditions, and to be aberrantly active in disease states including cancer, where consequences are pleiotropic with impact on cancer cell phenotypes and on the tumor immune microenvironment. Repeat element-derived RNAs play unique roles in exogenous and endogenous cell signaling under normal and disease conditions. A key component of repeat element-derived transcript-dependent signaling occurs via triggering of innate immune receptor signaling that then feeds forward to inflammatory responses through interferon and NFκB signaling. It has recently been shown that cancer cells display abnormal transcriptional activity of repeat elements and that this is linked to either aggressive disease and treatment failure or to improved prognosis/treatment response, depending on cell context and the amplitude of the so-called 'viral mimicry' response that is engaged. 'Viral mimicry' refers to a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons and other repeat elements. In this paper, the literature regarding transcriptional activation of repeat elements and engagement of inflammatory signaling in normal (focusing on hematopoiesis) and cancer is reviewed with an emphasis on the role of innate immune receptor signaling, in particular by dsRNA receptors of the RIG-1 like receptor family and interferons/NFκB. How repeat element-derived RNA reprograms cell identity through RNA-guided chromatin state modulation is also discussed.

Keywords: RNA-guided chromatin regulation; histone H3 lysine 9 trimethylation; immune checkpoint blockade; innate immunity; p53; repetitive elements; satellite repeats; viral mimicry.

Publication types

Review

Grants and funding

Research funding in the Callanan and Delva laboratory is from the ITMO Cancer Epigenetics and Cancer program, Fondation ARC, ANR-Labex ‘Lipstic’, the Région Bourgogne Franche Comté and Fonds Feder (ReHETlym). B.P. and C.S. have been funded by doctoral stipends from the French ministry for research and higher education and the Fondation pour la Recherche Médicale, respectively. C.S. has obtained additional doctoral funding from the French Society for Hematology and Fondation ARC.