Epigenetic reprogramming through histone 3 lysine 9 posttranslational modifications in hyperuricemia-associated inflammation - EpiHUI

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Project title: Epigenetic reprogramming through histone 3 lysine 9 posttranslational modifications in hyperuricemia-associated inflammation

Acronym: EpiHUI

Competition: P1 – Development of the national R&D system - Postdoctoral Research Projects (PD)

Project code: PN-III-P1-1.1-PD-2019-0802

Project duration: 24 months (01/10/2020 - 30/09/2022)

Budget: 246.949,00 lei

Coordinator: “Iuliu Hațieganu“ University of Medicine and Pharmacy, Cluj-Napoca – RO, Medical Genetics

Project director: Assist. prof. Tania O. Crișan, MD, PhD

Abstract

Uric acid is the end-product of the purine catabolic pathway in humans which results in higher levels of the ionised form, urate, in the blood compared to other mammals. In hyperuricemia (typically serum urate above 7 mg/dL), urate precipitates in tissues forming needle-shaped crystals. Crystals of monosodium urate (MSU) are triggers of the inflammatory attacks clinically observed in gouty arthritis.Gout is the most common form of inflammatory arthritis and is increasing in relevance due to its rising prevalence and incidence.
Growing evidence suggests that increased concentrations of urate also contribute to other inflammatory/metabolic diseases (e.g. metabolic syndrome, atherosclerosis). Our hypothesis is that human monocytes can be primed by urate treatment for elevated responses of proinflammatory cytokines and low anti-inflammatory IL-1 receptor antagonist. Preliminary unpublished data from our group identified that these effects of uric acid exposure can be reversed by inhibitors of the EHMT2 enzyme (euchromatic histone lysine methyl trasferase 2). This enzyme is involved in laying down methylation marks at histone 3 lysine 9 (H3K9) residues, which is associated with gene silencing. The expected outcome of the current proposal, is to set up a translational study, using in vitro and ex vivo approaches in patients, to test for H3K9 dependent epigenetic mechanisms in urate-mediated inflammation. The expected impact of this project lays in the observation that soluble urate could also have epigenetic modulatory effects on the cytokine production of human innate immune cells. This challenges the current dogma that urate induces gout solely via crystal deposition, it can impact strategies for disease progression and could drive development of new therapeutic targets relevant for gout and for other diseases.

Project objectives

The overall aim of this project is to assess whether the methylation of lysine 9 in histone 3 (H3K9) (monomethylation H3K9me1, di-methylation H3K9me2, tri-methylation H3K9me3) is different in patients with hyperuricemia as a potential mechanism for the persistence of elevated serum urate effects.
Three specific complementary objectives will be pursued:

  1. Replication and validation of in vitro pilot data showing inflammatory capacity of urate-treated monocytes as modulated by EHMT2 inhibition
  2. Evaluation of H3K9me1, H3K9me2 and H3K9me3 in cells treated with urate or in vitro control media and integration with functional data (gene transcription and cytokine production)
  3. Evaluation of H3K9me1, H3K9me2 and H3K9me3 in circulating monocytes of volunteers with normouricemia (control group) and volunteers with hyperuricemia (study group) and integration with clinical and experimental data

Publications

  1. Badii M, Gaal OI, Cleophas MC, Klück V, Davar R, Habibi E, Keating ST, Novakovic B, Helsen, Dalbeth N, Stamp LK, Macartney-Coxson D, Phipps-Green AJ, Stunnenberg HG, Dinarello CA, Merriman TR, Netea MG, Crişan TO#, Joosten LAB# (equal contribution), Urate – induced epigenetic modifications in myeloid cells, Arthritis Research and Therapy, july 2021 DOI: 10.1186/s13075-021-02580-1 (ISI impact factor 4,269) https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-021-02580-1 
  2. Nica V, Popp RA, Crişan TO#, Joosten LAB# (equal contribution), The future clinical implications of trained immunity. Expert Rev Clin Immunol. 2022 Sep 18:1-10. doi: 10.1080/1744666X.2022.2120470. (ISI factor impact 4,57) https://www.tandfonline.com/doi/full/10.1080/1744666X.2022.2120470 
  3. Badii M, Gaal O, Popp RA, Crişan TO#, Joosten LAB# (equal contribution), Trained immunity and inflammation in rheumatic diseases. Joint Bone Spine. 2022 Jul;89(4):105364. doi: 10.1016/j.jbspin.2022.105364. (ISI factor impact 5,263) https://www.sciencedirect.com/science/article/pii/S1297319X22000239?via%3Dihub 

Conferences (oral)