ERA Chair - RNA and Immunity - Mary O'Connell

Research areas

• Identification of novel RNA editing/RNA modification events in RNA
• Investigating the biological function of nucleotide modification in innate immunity
• Elucidating the role RNA modification in disease

Main objectives

• To define the prevalence and biological function of RNA modification in RNA.
• To establish in vitro systems whereby the level of different RNA modification can be altered so that the global consequences can be studied.
• To determine if there are alterations in RNA modifications in autoimmune disorders.
• To investigate if ADAR2 has a role in innate immunity in the brain.

Content of research

Innate immunity and inflammation are central to human health. This was stated succinctly by the Nobel Laureate David Baltimore in 2011: ‘Autoimmunity, cancer and metabolic diseases are all secondary to chronic inflammation. This places inflammation at the heart of modern medicine’. The ‘Damage Model’ of Polly Matzinger proposes that innate immunity does not response to pathogens but responds to danger as defined by cellular damage. Therefore different cellular stresses can cause cellular damage, accidently triggering innate immunity which manifests itself as an autoimmune disease.

For many years my group has studied ADARs that convert adenosine to inosine in dsRNA. In 2014 we were the first to demonstrate that inosine in cellular RNA allows the cell to discriminate between self and non-self RNAs. We showed that the Adar1^-/-embryo is dead by day E12.5 as it lacks hematopoietic progenitor cells and has elevated interferon levels. However this mutant can be rescued by a mutation in Mavs^-/- demonstrating that Adar1 is an essential component of the innate immune pathway.

There are over 140 different types of RNA modification so we propose that RNA modifications other that inosine play a role in the innate immune response. Therefore we want to isolate and identify different classes of RNAs (not tRNAs and rRNAs) which are enriched in RNA modification, investigate their biological functions if their levels change in autoimmune disorders.

list / cards

SELECTED PUBLICATIONS

2017

• GALLO, A; VUKIC, D; MICHALIK, D; O'CONNELL, MA; KEEGAN, LP, 2017:ADAR RNA editing in human disease; more to it than meets the I. HUMAN GENETICS 136 (9), p. 1265 - 1278.
• KEEGAN, L; KHAN, A; VUKIC, D; O'CONNELL, M, 2017:ADAR RNA editing below the backbone. RNA 23 (9), p. 1317 - 1328.
• QUIN, JE; BUJILA, I; CHERIF, M; SANOU, GS; QU, Y; HOMANN, MV; ROLICKA, A; SIRIMA, SB; O'CONNELL, MA; LENNARTSSON, A; TROYE-BLOMBERG, M; NEBIE, I; FARRANT, AKO, 2017:Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria. ELIFE 6

2015

• M. A. O’CONNELL; N. MANNION; L.P. KEEGAN, 2015:The Epitranscriptome and Innate Immunity. PLoS Genetics 12 (11)
• MANNION, N; ARIETI, F; GALLO, A; KEEGAN, LP; O'CONNELL, MA, 2015:New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins. BIOMOLECULES 5 (4), p. 2338 - 2362.

2014

• MANNION, NM; GREENWOOD, SM; YOUNG, R; COX, S; BRINDLE, J; READ, D; NELLAKER, C; VESELY, C; PONTING, CP; MCLAUGHLIN, PJ; JANTSCH, MF; DORIN, J; ADAMS, IR; SCADDEN, ADJ; OHMAN, M; KEEGAN, LP; O'CONNELL, MA, 2014:The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA. CELL REPORTS 9 (4), p. 1482 - 1494.

2013

• RAMASWAMI, G; ZHANG, R; PISKOL, R; KEEGAN, LP; DENG, P; O'CONNELL, MA; LI, JB, 2013:Identifying RNA editing sites using RNA sequencing data alone. NATURE METHODS 10 (2), p. 128 - 132.

2012

• RICE, GI; KASHER, PR; FORTE, GMA; MANNION, NM; GREENWOOD, SM; SZYNKIEWICZ, M; DICKERSON, JE; BHASKAR, SS; ZAMPINI, M; BRIGGS, TA; JENKINSON, EM; BACINO, CA; BATTINI, R; BERTINI, E; BROGAN, PA; BRUETON, LA; CARPANELLI, M; DE LAET, C; DE LONLAY, P; DEL TORO, 2012:Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. NATURE GENETICS 44 (11), p. 1243 - 1248.

2011

• MARCUCCI, R; BRINDLE, J; PARO, S; CASADIO, A; HEMPEL, S; MORRICE, N; BISSO, A; KEEGAN, LP; DEL SAL, G; O'CONNELL, MA, 2011:Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO JOURNAL 30 (20), p. 4211 - 4222.

2010

• GALEANO, F; LEROY, A; ROSSETTI, C; GROMOVA, I; GAUTIER, P; KEEGAN, LP; MASSIMI, L; DI ROCCO, C; O'CONNELL, MA; GALLO, A, 2010:Human BLCAP transcript: new editing events in normal and cancerous tissues. INTERNATIONAL JOURNAL OF CANCER 127 (1), p. 127 - 137.

2009

• HEALE, BSE; KEEGAN, LP; MCGURK, L; MICHLEWSKI, G; BRINDLE, J; STANTON, CM; CACERES, JF; O'CONNELL, MA, 2009:Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO JOURNAL 28 (20), p. 3145 - 3156.