SATB2 regulation of neuronal nuclear architecture

Gene transcription as a key component of long-term memory and adaptation to novel environments, collectively known as neuroplasticity. The aim of this project is to investigate how the precise arrangement/spatial distribution of chromatin (the DNA packed with proteins) in the nucleus, referred to as nuclear architecture, affects the gene transcription relevant for learning and memory. To shed light on this processes, we will use as a model case SATB2, a highly conserved nuclear protein that binds to DNA and controls the DNA looping. In a DNA looping event, chromatin forms physical loops that bring together gene regulatory elements, e.g. enhancers and promoters that are otherwise separated by large distances. The interactions between these elements at the anchors of the DNA loops allow for fine-tuning of gene transcription. In mice, the ablation of Satb2 gene leads to deficiencies in various forms of long-term memory. In humans, SATB2 is a schizophrenia risk locus and is associated with cognitive ability. Mutations in only one of the two SATB2 alleles causes the SATB2- associated syndrome, a genetic disease characterized by severe intellectual disability. Thus, gaining deeper insights into the molecular function of SATB2 in the brain will expand our understanding of the molecular mechanisms underlying cognitive functions and dysfunctions and will enable the design of more effective therapeutics for neuropsychiatric diseases. In our project, we will employ state-of-the art functional genomics assays to measure molecular activities such as gene expression, protein-DNA interactions, and three-dimensional chromatin folding on a genome-wide scale in wild type vs. SATB2 knockout neurons, under baseline conditions and upon increased neuronal activity. These experiments will reveal if SATB2-steered chromatin looping and/or association with the nuclear envelope influence gene expression that underlies long-term neuronal plasticity.

Cerebral cortex and hippocampus are the "work horses" of cognitive performance. Special neurons in these brain regions contain the protein SATB2. If the SATB2 gene is mutated, the IQ drops to less than 40. Our team has succeeded in depicting the three-dimensional (3D) structure of DNA with and without SATB2. We found that SATB2 alters the 3D structure of specific gene regions whose sequence is associated with the risk of neuropsychiatric disorders such as dementia or schizophrenia. In many neuropsychiatric disorders, such as dementia or schizophrenia, cognitive processes and thus learning and memory performance in the brain are impaired. Our team has been investigating these symptoms for many years by focusing on the role of the protein SATB2. In collaboration with our colleagues from University of Galway and Mount Sinai at New York, we were able to demonstrate that the presence of SATB2 in the nucleus of certain neurons in the cerebral cortex fundamentally influences and organizes the specific 3D structure of the DNA of these neurons. If the protein is missing, the order in the genetic material necessary for cognitive performance is disrupted.