Role of genome organizer Satb2 in adult brain function

Satb2 is a transcriptional regulator that binds to AT-rich DNA sequences of multiple gene loci, alters chromatin architecture and targets chromatin remodeling/modifying complexes over long distances. SATB2 haploinsufficiency in humans causes severe learning difficulties and profound mental retardation, so far explained by developmental defects in the establishment of cortico-cortical connections. Based on our previous findings demonstrating an important role of Satb2 in PNS neurotransmitter plasticity, and our preliminary data about neuronal activity/BDNF-driven Satb2 expression, we propose a novel function of Satb2 in long-term plasticity processes in adult CNS. We hypothesize that Satb2 is employed by postmitotic neurons as a regulator of activity- driven adaptive gene transcription, which is the basis of consolidating and stabilizing cognitive-behavioral memories. Thus, our new concept for the function of Satb2 in mature brain provides an alternative explanation for the cognitive defects caused by SATB2 haploinsufficiency. To study the role of Satb2 in higher brain function we will make use of conditional knockout models (the complete Satb2 knockouts die perinatally). Mice carrying floxed Satb2 allele (generated by us) will be crossed with specific Cre deleters to achieve conditional Satb2 deletion in forebrain excitatory neurons. To test our hypothesis we will analyze the effect of Satb2 deletion on hippocampal synaptic plasticity; learning and memory behaviour; excitatory synaptogenesis, dendritic morphology and spine density, the latter being strong indicators of structural synaptic plasticity. Furthermore, by employing bioinformatics approaches, such as transcriptome profiling and deep sequencing for analysis of in vivo Satb2- binding sites we aim at dissecting the gene-expression programs downstream of Satb2. Together, these experiments will help elucidating the function of Satb2 in adult brain - currently completely unknown - at molecular, cellular, synaptic and animal behavioral level. The results of the proposed work will provide novel insights into the role of chromatin structure regulators like Satb2 in coordinating the activity-dependent transcriptional responses that underlie long-lasting alterations in brain circuits.

Special AT-rich sequence binding protein 2 (Satb2) is an epigenetic regulator that binds to DNA and recruits chromatin-modifying complexes to the anchorage sites. Moreover, it has the potential to alter higher-order chromatin architecture by mediating the formation of DNA loops. Human patients with Satb2 haploinsufficiency suffer from cognitive deficits and a human Satb2 allele has recently been identified as conferring a high risk for schizophrenia. The precise function of Satb2 in the adult CNS and the molecular mechanisms of its action have so far remained elusive. By employing a novel conditional knockout model and a battery of behavior, electrophysiological and molecular analyses we now provide first evidence for a key function of Satb2 as a regulator of cognitive processes in the mature brain. We found out that ablation of Satb2 from the adult mouse forebrain causes deficits in long-term fear and object discrimination memory. Consistent with these behavioral defects, long-term potentiation at Schaffer collateral CA3-CA1 synapses, which is considered as a molecular correlate of memory, was also deficient in acute hippocampal slices from conditional mutants. At mechanistic level, we found that synaptic activity and BDNF up-regulate Satb2, which itself binds to promoters of coding and noncoding genes. Satb2 controls the expression of a large cohort of miRNAs in adult hippocampus, many of which are implicated in synaptic plasticity and memory formation. These findings establish Satb2 as a previously unsuspected nuclear component of the machinery that determines the production of new proteins in neurons. Since activity-dependent protein synthesis is essential for learning and memory and since its dysfunction is a core feature of various psychiatric disorders, our study is likely to contribute to the understanding of the underlying pathophysiological mechanisms of both SATB2-associated syndrome and some relevant neuropsychiatric diseases.