Genome and Stem Cell Plasticity in Development and Ageing

 Jean-Marc LEMAITRE

 IRMB - U 1183

 80 rue Augustin Fliche, 34295 Montpellier

Phone: +33 4 67 33 04 52

Email: jean-marc.lemaitre@inserm.fr

Website

Cellular senescence which contributes to aging and restricts longevity, is associated to physiological and morphological changes, leading to a robust cell cycle arrest and alteration of tissues homeostasie. Important and specific associated changes in genome organization suggest the possible existence of an epigenetic control of senescence and aging that we study in following gene expression and replication programs. To better understand these specific regulations, we developed different strategies and models in human cells for induction and reversion of the senescent phenotype. We performed an siRNA screen to identify genes associated to chromatin metabolism, whose downregulation is involved in senescence induction or reversion and developed strategies based on the iPSC technology to reprogram cells from aged donors, to evaluate their ability to erase cellular stigmas of senescence/aging.

The main objective of our laboratory is to analyse the impact of an epigenetic control of senescence in aging in following the expression and replication of the genome. We integrate different levels of analysis, from DNA sequence to local chromatin organization and to nuclear architecture to evaluate the limits of the cell plasticity during aging and rejuvenation experiments from human cells. We believe it may lead to define new strategies to correct some pathologies related to aging.

Keywords: Senescence chromatin replication reprogramming, Stem cells

Main publications

• Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes and Dev. 2011 Nov 1;25(21):2248-53.
• Prieur A, Besnard E, Babled A, Lemaitre JM. p53/p21CIP1 and p16INK4A independent induction of senescence by a Chromatin dependent alteration of S- phase progression in absence of DNA damage. Nat Commun. 2011 13 Sept. 2:473. DOI: 10.1038/ncomms1473
• Ramirez JM, Gerbal-Chaloin S, Milhavet O, Bai Q, Becker F, Assou S, Lemaitre JM, Hamamah S, De Vos J. Benchmarking Human Pluripotent Stem Cell Markers During Differentiation into the Three Germ Layers Unveils A Striking Heterogeneity. Stem Cells. 2011 Jun 28. doi: 10.1002/stem.681.
• Krasinska, l., Besnard, E., Cot, E., Dohet, C., Méchali, M., Lemaitre JM. and Fisher. D. Cdk1 and Cdk2 activity levels determine the efficiency of replication origin firing in Xenopus. EMBO J. 2008 7 vol 24 7 Feb 2008 1-125
• Cuvier, O., Stanojcic, S., Lemaitre, JM. and Mechali, M. A Topoisomerase II-dependent mechanism for resetting replicons at the S-M phase transition. Genes and Dev. 2008 vol 22 n°7, p860-865.
• Stanojcic, S., Lemaitre, JM., Brodolin, K., Danis, E., and Mechali, M.. In Xenopus egg extracts, DNA replication initiates preferentially at or near AT asymetric sequences. Mol. Cell Biol. 2008 vol 28 n°17, p5265-5274.
• Lemaitre, JM., Danis E., Pasero P. Vassetzky, Y. and Méchali., M. Mitotic remodeling of the replicon and chromosome structure. Cell 2005, 123: 787-801.
• Lemaitre, JM., and Méchali, M. Organisation and Dynamics of the Cell Nucleus for DNA Replication. Vision of the Nucleus. Text Book 2004, Edited by Hemmerich, P and Dieckmann, S. American Scientific Publisher 2004 : 37-51.
• Lemaitre, JM., Bocquet, S., and Méchali. M. Competence to replicate in the unfertilized egg is conferred by cdc6 during meiotic maturation. Nature. 2002,19: 718-722.
• Maiorano, D., Lemaitre, JM., and M. Méchali. M. Stepwise Regulated chromatin Assembly of MCM2-7.
• J. Biol. Chem. 2000, 275: 8426-8431.