Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states

Ricardo Martins-Ferreira; Josep Calafell-Segura; João Chaves; Laura Ciudad; António Martins da Silva; Paulo Pinho E Costa; Bárbara Leal; Esteban Ballestar

doi:10.1016/j.isci.2024.110546

Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states

iScience. 2024 Jul 20;27(8):110546. doi: 10.1016/j.isci.2024.110546. eCollection 2024 Aug 16.

Authors

Ricardo Martins-Ferreira^{1

2

3

4}, Josep Calafell-Segura¹, João Chaves^{3

4

5}, Laura Ciudad¹, António Martins da Silva^{3

4

6}, Paulo Pinho E Costa^{2

3

4

7}, Bárbara Leal^{2

3

4}, Esteban Ballestar^{1

8}

Affiliations

¹ Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain.
² Immunogenetics Laboratory, Molecular Pathology and Immunology Department, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UPorto), 4050-313 Porto, Portugal.
³ Autoimmunity and Neuroscience Group. Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
⁴ ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.
⁵ Neurology Service, Centro Hospitalar Universitário de Santo António (CHUdSA), 4099-001 Porto, Portugal.
⁶ Neurophysiology Service, CHUdSA 4099-001 Porto, Portugal.
⁷ Department of Human Genetics, Instituto Nacional de Saúde Dr. Ricardo Jorge 4000-055 Porto, Portugal.
⁸ Epigenetics in Inflammatory and Metabolic Diseases Laboratory, Health Science Center (HSC), East China Normal University (ECNU), Shanghai 200241, China.

Abstract

Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression.

Keywords: Epigenetics; Epilepsy; Microglia; Purines; Transcriptomics.