Research
PREVIOUS AND CURRENT RESEARCH
Cerebral organoids as new models to study human neurogenesis. The generation of human brain organoids from induced pluripotent stem cells enables the investigation of human neural progenitor cells (SOX2/red) and neurons (TUJ1/green).
Epigenetic regulation of neocortex development
During the development of the mouse neocortex, stem and progenitor cells initially proliferate, then sequentially give rise to neurons destined to different cortical layers and finally switch to gliogenesis resulting in the generation of astrocytes and oligodendrocytes. Precise spatial and temporal regulation of neural progenitor differentiation is key for the proper formation of the complex structure of the neocortex. An impairment of the development of the brain, as observed in patients with neurodevelopmental disorders, is frequently linked to compromised intellectual abilities.
Chromatin modifiers of the Polycomb group of proteins are known to regulate several different aspects of neocortex development (Albert and Huttner, 2018). By epigenome profiling in specific neural cell populations, we have shown that Polycomb and Trithorax-mediated histone methylation is highly dynamic during neocortex development (Albert et al., 2017). Moreover, by CRISPR/Cas9-based epigenome editing in vivo, we could show that altering histone methylation at a specific promoter was sufficient to reduce the expression of a key neural transcription factor resulting in altered neural progenitor abundance (Albert et al., 2017). We are continuing to develop tools for in vivo epigenome editing, enabling gene-specific functional studies of epigenetics in the developing brain.
Evolutionary expansion of the neocortex
Interspecies differences in both neuron number and neocortex size are thought to arise from differences in the proliferative capacity and the abundance of neural progenitor subtypes. Specifically, one progenitor type, the basal radial glia, is particularly abundant in mammals with a large, folded neocortex and is characterized by extensive self-renewal and proliferative capacities. Transcriptome studies in different mammalian species have uncovered genes that are expressed in human basal radial glia, among which are human-specific genes that may have contributed to neocortex expansion during evolution (Florio et al., 2015; Florio et al., 2018; Kalebic et al, 2018). However, the gene regulatory mechanisms that orchestrate specific gene expression programs from the genomic DNA in different neural progenitor cell types in different species remain poorly understood.
Gene transcription is initiated at promoter sequences immediately upstream of a gene, but differential gene expression in specific cell types is controlled by often distally located regulatory elements. This complex regulatory landscape allows cells to respond to developmental and environmental stimuli. Interestingly, genome-wide association studies have uncovered that more than 90% of disease-associated variants lie in non-coding DNA, suggesting that dysregulation of gene expression contributes to disease (Krijger and de Laat, 2016). We are studying gene regulation using in vivo models as well as novel in vitro human induced pluripotent stem cell-derived 3D brain organoids. Our work aims to provide new insights into gene regulatory mechanisms with implications for neocortex evolution as well as neuropathologies.
Our research was covered by the EU research magazine:
https://e.issuu.com/embed.html?d=interrogating_the_gene_regulatory_code_eur29_h_res&u=euresearcher