Blanc SVSE 6 - Blanc - SVSE 6 - Génomique, génétique, bioinformatique et biologie systémique

Androgen target genes in nervous system: an approach to study sex bias in neurodevelopmental diseases – HARTaGeNe (Human AR Target Genes in Neur

Androgen exposition during brain development and gender bias in autism and intellectual disability

Can the effect of androgen exposition on the expression of key genes during brain development be the cause of the excess of boys affected by autism and intellectual disability?

Overlap between androgen target genes and genes involved in brain development/diseases

The original question addressed in this project concerns the gender bias (male excess) observed in different diseases of neuronal development such as autism, mental retardation or Hirschsprung's disease (1.4 to 4 times more boys affected than girls), and how the effects of androgens may play a role in these biases. More generally, the project should provide new insights into the molecular mechanisms involved in the establishment of sexual dimorphism in the human brain. We propose to address this problem by systematically analyzing the action of androgens on gene expression in human neurons, as very little attention has been given so far. The idea is to identify whether there is an overlap between the target genes (and pathways) regulated by androgens and the genes involved in brain development, including those involved in the sex-bias neurodevelopmental diseases. The project will also focus on understanding the role of the androgen receptor in the human brain male by analyzing its expression during two critical periods of physiological androgen exposure (the 2nd trimester of fetal life and and the first months after birth).

We will study the action of androgens in neurons differentiated from human embryonic stem cells. The effect of androgens on gene expression will be analyzed on these cells by chromatin immunoprecipitation with androgen receptor antibody combined with high-throughput sequencing (ChIPseq), as well as transcriptomic analysis (using chips but also RNA sequencing technique). We will also analyze androgen effects at the cellular level, and will pay particular attention to their effect on the development of dendrites or the establishment of synapses. We will experimentally validate these results on selected genes, and analyze them in terms of functional pathways. We will compare the target genes and pathways regulated by androgens to those involved in sex-bias neurodevelopmental diseases using data from sequencing or association studies. We will look if polymorphisms or rare variants could affect the regulation of these target genes by androgens, and establish collaborations to the association between theses variants and the diseases in case/control cohorts. To better understand the role of the androgen receptor in the human male brain development during the two critical physiological androgen exposure periods, we will analyze its expression and expression of its target genes by in situ hybridization and immunocytochemistry in the human fetal and neonatal brain.

This project will generate a list of genes whose expression is regulated by androgens and the androgen receptor in neuronal cells, and characterize their expression profiles during periods where the developing brain is exposed to androgens. In this list we hope to identify both genes already implicated in sex-bias neurodevelopmental diseases (autism, intellectual disability, Hirschsprung's disease) but also new potential candidate genes for these diseases as well as functional polymorphisms / variants affecting their regulation by androgens and associated to these diseases.

We hope to shed light on some molecular mechanisms underlying the difference in susceptibility between men and women in certain brain diseases, neurodevelopmental disorders (autism, intellectual disability, Hirschsprung's disease) or even neurodegenerative diseases (amyotrophic lateral sclerosis). This will increase knowledge about the pathophysiological mechanisms leading to these very disabling diseases. Better understand why men are more affected than women by these diseases and better understand the role played by androgens in this difference will be particularly important for the development of potential treatments for these diseases.

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The original question of this project is how the effect of androgens in brain can play a role in the major sex biases observed in different neurodevelopmental diseases (notably autism, mental retardation, Hirschsprung disease (congenital aganglionic megacolon)). More generally, this should shed light on molecular mechanisms implicated in generating during brain development gender dimorphism. We propose to address this issue by increasing knowledge about the action on gene expression of androgens in human neurons, which has been poorly studied until now. We will produce large quantities of human iPS (reprogrammed) cells, differentiate them in neurons and test the effect of androgens on gene expression, notably using Androgen Receptor (AR) ChIPseq (Chromatin Immunoprecipitation) and transcriptome analysis, but also on downstream cellular phenotypes. We will validate findings, analyse them in terms of pathways, and search for transcription factors that may cooperate with AR in neurons. We will compare AR target genes and pathways to those implicated in neurodevelopmental sex biased diseases such as MR, autism, Hirschsprung disease (CNVs, mutations or GWAS datas), search for SNPs and rare variants that may affect AR recognition in target genes, and establish collaborations to test them in patient/control cohorts. To better understand the role of AR in brain development during the two critical early periods of androgen exposition, we will complete the analysis by looking at the expression in fetal and neonatal human brain, by ISH and/or immunohistochemistry, of AR and other potential inducers of sex dimorphism (sry, AMH, AMHRII, etc) and of particularly interesting AR targets.

This project associates four teams with documented complementary expertise in gene expression studies using genome wide state of the art strategies, human genetics, bioinformatics, generation of human iPS cells, their differentiation, and use in cell biology studies, and in fetopathology and analysis of gene expression in the developing human brain.


Project coordination

Jean-Louis MANDEL (CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM) – jlmandel@igbmc.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGBMC CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM
IGBMC CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM
IGBMC CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM
HRD-APHP INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION PARIS VII

Help of the ANR 368,000 euros
Beginning and duration of the scientific project: - 36 Months

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