The French National Centre for Scientific Research


Transcriptional and epigenetic signatures of opiates


Project leader : Pierre-Eric LUTZ

Opiates such as morphine and heroin have been both a benediction and a curse to mankind for centuries. While they remain the most efficient and prescribed painkillers in modern medicine, their chronic use also leads in some individuals to the emergence of addiction. Once hooked, affected individuals face a lifetime struggle to control, and hopefully abstain from, opiate consumption.

A major challenge is to understand how opiates can have such devastating and protracted effects on human behaviour. Our current projects seek to answer this important clinical and societal question, by exploring the hypothesis that epigenetic mechanisms may be critically implicated in these processes. Epigenetic mechanisms, such as DNA methylation and histone marks, correspond to chemical modifications that do not modify the DNA sequence, but control structural and functional organization of the genome. While they have been primarily implicated in cellular differentiation, accumulating data indicates that they remain active throughout life, even in post-mitotic neurons of the adult brain, where epigenetic reprogramming is progressively associated with a series of psychiatric phenotypes, including depression, addiction, and others.

In this context, our animal research program proposes to focus on the role of DNA methylation, a major epigenetic mark, in opiate effects.To do so, we combine genetic tools that we develop in the mouse, with next-generation sequencing methodologies and behavioural testing. Our goal is to produce comprehensive characterizations, in the entire genome, of DNA methylation, histone and gene expression adaptations that are triggered by opiates. Furthermore, we seek to characterize how these molecular substrates contribute to behavioural effects of opiates, focusing on their “dark side”: the potent aversive aspects of drug withdrawal, and the emergence of emotional dysfunction during prolonged abstinence from the drug.

Importantly, we are developing experimental strategies to conduct cell-type specific analyses of the neuronal population that expresses the mu opioid receptor, and represents the primary target of opiates. This endeavour is driven by the recognition that the mammalian brain is composed of multiple intermingled cell-types that exhibit huge transcriptomic and epigenetic diversity. This complexity severely hampers the detection of subtle cell-type specific processes that account for psychiatric symptoms, and go undetected otherwise. Implementing cell-type specific strategies is therefore critical, and our strategy has the potential to define the epigenetic blueprint of opiates with unprecedented resolution. In the long-term, we hope that this work will represent a main step forward for the understanding of opiate powerful properties.



Members

Pierre-Eric Lutz
(Researcher)
E-mail
 
Camille Falconnier
(PhD student)
 
Amazigh Mokhtari
(PhD student)
 
Pierre Hener
(Study Engineer, IE)
 
Charles Decraene
(Research Engineer, IR)
 
Alba Caparros-Roissard
(Study Engineer, IE)
 

Collaborators

  • Raoul Belzeaux, El Chérif Ibrahim, Eduardo Gascon (Institut de Neurosciences de la Timone, Marseille, France)
  • Andrée Delahaye-Duriez (AP-HP, Neurodiderot Inserm UMR 1141, Paris, France)
  • Bruno Etain & Cynthia Marie-Claire (Université Paris Descartes, INSERM UMR 1144, Paris, France)
  • Brigitte Kieffer (Douglas Hospital Research Centre, McGill University, Montréal, Canada)
  • Karine Merienne & Anne-Laurence Boutillier (Laboratoire de Neurosciences Cognitives et Adaptatives, CNRS UMR 7364, Strasbourg, France)
  • Gustavo Turecki (McGill Group for Suicide Studies, Douglas Hospital Research Centre, McGill University, Montréal, Canada)
  • Benoit Labonté (CERVO Institute, Laval University, Québec, Canada)

Methodological approaches

  • Genetically modified mice (knock-out and knock-in for opioid receptors)
  • Next-generation sequencing (RNA-Seq, WGBS, RRBS, ChIP-Seq)
  • Quantitative PCR, immunohistochemistry
  • Behavioral models: opiate precipitated withdrawal-induced aversion; spontaneous opiate withdrawal and emotional consequences of abstinence
  • Behavioral tests (social interactions, forced swim, sucrose preference)

Funding

  • Agence Nationale pour la Recherche (ANR)
  • Fondation pour la Recherche sur le Cerveau (FRC)
  • Union Nationale des Familles et Amis de personnes Malades et/ou Handicapées Psychiques (UNAFAM)
  • Fondation pour la Recherche médicale (FRM équipe)
  • Fondation de France
  • American Foundation for Suicide Prevention (AFSP)

Selected publications

Lutz PE, Chay MA, Pacis A, Chen GG, Aouabed Z, Maffioletti E, Theroux JF, Grenier JC, Yang J, Aguirre M, Ernst C, Redensek R, van Kempen L, Yalcin I, Kwan T, Mechawar N, Turecki G (2021) Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation. Nature Communications 12(1):1132

Lutz PE, Almeida D, Filliol D, Jollant F, Kieffer BL, Turecki G (2021) Increased functional coupling of the mu opioid receptor in the anterior insula of depressed individuals. Neuropsychopharmacology 46(5):920-927

Lutz PE, Gross JA, Dhir SK, Maussion G, Yang J, Bramoulle A, Meaney MJ, Turecki G (2018) Epigenetic regulation of the kappa opioid receptor by child abuse. Biological Psychiatry 84:751-761

Belzeaux R, Lalanne T, Kieffer BL, Lutz PE (2018) Focusing on the opioid system for addiction biomarker discovery. Trends in Molecular Medicine 24:206-220

Lutz PE, Mechawar N, Turecki G (2018) Neuropathology of suicide: recent findings and future directions. Molecular Psychiatry 22:1395-1412

Lutz PE, Tanti A, Gasecka A, Barnett-Burns S, Kim JJ, Zhou Y, Chen GG, Wakid M, Shaw M, Almeida D, Chay M-A, Yang J, Larivière V, M’Boutchou M-N, van Kempen L, Yerko V, Prud’homme J, Davoli MA, Vaillancourt K, Théroux J-F, Bramoullé A, Zhang TY, Meaney MJ, Ernst C, Côté D, Mechawar N, Turecki G (2017) Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence. American Journal of Psychiatry 174:1185-1194

Lutz PE, Ayranci G, Chu-Sin-Chung P, Matifas A, Koebel P, Filliol D, Befort K, Ouagazzal AM, Kieffer BL (2014) Distinct mu, delta and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology 39:2694-705

Lutz PE, Kieffer BL (2013) Opioid receptors: distinct roles in mood disorders. Trends in Neurosciences 36:195-206

 


 
The French National Centre for Scientific Research