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Laboratory | Epigenetics | Brain | Alzheimer's disease | Cognition | Genomics


LEM

Mammalian Epigenomics Laboratory

Published on 12 April 2017
Accurate control of genome expression is crucial for proper cell functioning. Our team is investigating how the epigenetic regulation of gene expression is altered in the brain during aging and Alzheimer’s disease, with the aim of identifying novel strategies for the treatment of cognitive impairment.

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Manager
Matthieu GERARD
+33 1 69 08 94 29
Matthieu.Gerard@Cea.Fr

 

 


Human resources
Matthieu GERARD, Researcher
Hélène PICAUD, Technician
Marina NOCENTE, Master 2 Student

RNA interference platform (PARi) is part of the lab
Scientific management
Matthieu GERARD (Researcher, CEA)
Operational management
Guillaume PINNA (Researcher, CEA)
Gueorgui KRATASSIOUK (Research Ingeneer, CNRS)
Marie VANDAMME (Technician, CEA)
Bioinformatic
Nadya MOROZOVA (Research Ingeneer, CNRS)


Gene targeting and animal facility

Patrick HERY, Technician, Platform manager
+33 1 69 08 94 32
patrick.hery@cea.fr

Anne-Sophie CHAPLAULT, Technician
+33 1 69 08 80 18
anne-sophie.chaplaut@cea.fr

Sylvain THESSIER, Technician
+33 1 69 08 80 18
sylvain.thessier@cea.fr

Jean-Charles ROBILLARD, Technician
+33 1 69 08 54 78
jean-charles.robillard@cea.fr


Our team is expert in the study of the mechanisms that regulate gene expression and access of the transcription machinery to the genome in its physiological chromatin environment (e.g. Houlard et al., 2006, PMID: 17083276; Chantalat et al., 2011, PMID: 21803857; Carrière et al., 2012, PMID: 21911356; Montellier et al., 2013, PMID: 23884607). The basic unit of chromatin, the nucleosome, is composed of 147 base pairs of DNA tightly wrapped around a core of eight histone proteins. Nucleosomal organization represents a strong physical barrier that prevents binding of most transcription factors to DNA. ATP-dependent chromatin remodeling factors (also called remodelers) are enzymes that control the density and positioning of nucleosomes on the genome. A major predicted function of these enzymes is to regulate access of the transcription machinery to the genome by generating (or suppressing) open chromatin regions at specific locations.

The goals of our research are three-fold :

Define how remodelers regulate genome accessibility and gene expression in three cell types

This three cell type differ in their state of pluripotency, differentiation and proliferation: embryonic stem (ES) cells, neuronal precursor cells and post-mitotic neurons. For this project, we have generated a collection of mouse ES cell lines, each expressing a tagged version of a remodeler. We are using genome-wide approaches including ChIP-seq (chromatin immunoprecipitation sequencing; Figure 1) and loss-of-function coupled to RNA-seq transcriptome analysis, to characterize the genome-wide distribution of remodelers and study their contribution to the regulation of gene expression. Our recent investigations revealed that remodelers have not only key functions in the control of transcriptional programs, but are also essential for the maintenance of the ES cell phenotype. We are currently investigating their functional specificities in neuronal precursor cells and neurons.

 
Figure 1. ChIP‑seq analysis of histone deacetylase 2 (HDAC2) binding on the mouse prenatal brain genome. (A) Heatmap representation of HDAC2 binding at 14,616 mouse promoters, rank-ordered from highest to lowest HDAC2 occupancy. Red colour means enrichment, white no enrichment. TSS: transcription start site. (B) HDAC2 binding profiles at the promoter of Gria2, Jun and Vamp3, which are examples of genes involved in memory formation or synaptic plasticity.

 

Analyze the impact of aging on chromatin remodeling and gene expression in the mouse brain.

We are testing the hypothesis that neuronal aging may be associated with progressive alterations of the nucleosomal barrier, resulting in changes in brain transcriptional programs.

 
 
Figure 2. Expression of HDAC2 in the adult mouse hippocampus, a brain region involved in memory formation. (A, B) HDAC2 was detected by anti-hemagglutinin (HA) immunofluorescence on brain sections from mice expressing HA-tagged HDAC2. (C) Neurons of the pyramidal cell layer are visualized by NeuN immunoreactivity. (D) HDAC2 is expressed in the pyramidal neurons of the hippocampus.
 
 

Identify and characterize the alterations in remodeler function at different stages of Alzheimer's disease using mouse models.

We are currently studying two remodelers that are the major binding partners of histone deacetylase 2 (HDAC2; Figures 1 and 2) in the brain. It has recently been shown that HDAC2 is overexpressed in Alzheimer's disease patients, resulting in repression of genes required for memory formation and synaptic plasticity, and in cognitive impairment (Gräff et al. 2012; PMID: 22388814). Our aim is to understand how chromatin remodeling and histone deacetylation contribute to dysregulation of genome expression at different stages of the pathology, and to identify novel pathways that could be targeted for early treatment of learning and memory deficits and prevention of cognitive decline.

 Publications