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Description
When neurons are stimulated, a cascade of intracellular signaling events alters the chromatin landscape, leading to changes in gene expression. This process is essential for activity-dependent plasticity, learning, and memory. Activity-regulated genes often engage in chromatin looping, bringing enhancers and promoters into proximity.
However, the precise mechanisms governing 3D epigenome remodeling, chromatin accessibility modifications, and the radial repositioning of activity-induced loci relative to the nuclear periphery remain unclear. While CTCF and Cohesin contribute to chromatin reorganization in all cell types, specific chromatin scaffolding proteins are hypothesized to regulate activity-dependent transcriptional programs in neurons.
To investigate these questions, we analyzed transcriptomic and 3D epigenomic changes in cortical neurons from floxed versus Satb2 cKO mice following increased neuronal activity. We have previously shown that SATB2, a DNA-binding protein, plays a crucial role in 3D genome organization in pyramidal neurons. Here, we assessed the genome-wide effects of neuronal activity on chromatin architecture at multiple hierarchical levels in the presence and absence of SATB2.
Our multi-omics integration revealed a profound deficiency in the activity-dependent regulome at both early (1h) and late (6h) time points after bicuculline treatment in Satb2 cKO neurons. This was accompanied by a loss of newly gained open chromatin regions and reduced enhancer-promoter interactions. In floxed neurons, neuronal activity triggered highly specific alterations in FIREs and superFIREs, local interaction hotspots enriched for synaptic function-related genes, which were severely impaired or absent in cKO neurons.
At larger hierarchical scales, bicuculline stimulation in floxed neurons led to increased chromatin compaction, stronger compartmentalization, and enhanced inter- and intra-chromosomal interactions, as well as intra-TAD interactions. These changes were strongly diminished in cKO neurons.
Our findings indicate that SATB2-dependent chromatin architecture remodeling is a key component of the molecular mechanisms underlying activity-regulated transcription in neurons.
| Author(s) | Nico Wahl*1, Mujahid Ali1, Georg Dechant1, and Galina Apostolova1 |
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| Affiliation(s) | 1 Institute for Neuroscience, Medical University of Innsbruck, Austria |
