Neural Stem Cell

Francois Guillemot : Transcriptional and epigenetic regulators of human brain development associated with neurodevelopmental disorders

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Illustration of our strategy to identify genes regulating human cerebral cortex development

Figure 1: Illustration of our strategy to identify genes regulating human cerebral cortex development and to characterise the pathological mechanisms associated with mutations in these genes. We focus on disease-causing genes that encode transcription factors and chromatin remodellers. To study their normal developmental functions, we identify their transcriptional targets by ChIP-Seq and RNA-Seq and we characterise the cellular processes they regulate by inactivating them in iPSC-derived neuronal cultures. To identify the pathological mechanisms underlying the neurodevelopmental disorders associated with these genes, we introduce the disease-causing mutations in iPSC-derived cultures by CRISPR/Cas9-mediated mutagenesis and we characterise the resulting defects in gene expression and cellular behavior.

Neuronal activity in the cerebral cortex underlies cognition and other fundamental functions of the human brain.

Mutations in genes with essential roles in development of the cerebral cortex result in neurodevelopmental disorders such as intellectual disability, autism and epilepsy.

We study the role of several neurodevelopmental disease-causing genes that code for transcription factors and chromatin remodelling factors, to gain insights into both the normal development of the human brain and the mechanisms that underlie prevalent disorders of human cognition.

Large scale sequencing of individuals with intellectual disability has revealed that heterozygous mutations in genes encoding subunits of the BAF SWI/SNF complex, including ARID1B and BCL11A, are among the most common causes of this pathology. The BAF SWI/SNF complex is a major regulator of chromatin remodelling and transcriptional regulation.

We have begun to elucidate the mechanisms by which loss of one copy of BCL11A or ARID1B affects brain development, using mouse models (Dias et al., 2016 and unpublished data). These mice recapitulate some of the anatomical and behavioural features of the disease in humans. Comparison of gene expression profiles in the brains of mutant and control mice has provided evidence for the involvement of these genes in transcriptional regulation in the developing and adult brain.

We are now extending these findings by studying the function of various disease-associated chromatin remodellers and transcription factors in human cerebral cortex development.

We use human foetal brain explants and iPSC-derived cortical cell culture to identify the direct transcriptional targets of these factors and the cellular processes that they regulate during cortical development.

We also characterise the mechanisms by which mutation of these factors results in dysregulation of target genes and in pathological development of the human cortex.