# CHMP7/ESCRT-III Is Localized at the Nuclear Envelope of Cortical Neurons and Required for Expression of Activity-Regulated Genes

## TL;DR

This study shows that a protein complex at the nuclear envelope helps regulate gene expression in response to neuronal activity, which is important for brain function and could be relevant to neurological disorders.

## Contribution

The study identifies CHMP7/ESCRT-III as a novel component of a nuclear tether involved in activity-dependent gene regulation in cortical neurons.

## Key findings

- Increased neuronal activity correlates with accumulation of CHMP7 and CHMP4B at the nuclear envelope.
- Reducing CHMP7 levels decreases expression of genes related to neuronal activity and synaptic communication.
- Transcriptome changes in Chmp7 knockdown models mirror those in Satb2 and Lemd2 loss-of-function models.

## Abstract

Neurons in the brain constantly change their activity in response to experience, and this activity must be translated into changes in gene expression to support learning, memory, and normal brain function. How this communication between neuronal activity and the cell nucleus is organized is still not fully understood. In this study, we investigated how proteins at the boundary of the nucleus help regulate activity-dependent gene expression in cortical neurons. We focused on proteins that form a physical connection between DNA and the nuclear envelope, the membrane that surrounds the nucleus. We found that increased neuronal activity is associated with the accumulation of specific membrane-remodeling proteins at the nuclear envelope. Reducing the levels of one of these proteins led to widespread decreases in genes involved in neuronal activity and synaptic communication. Importantly, these gene expression changes closely matched those seen when other components of the same nuclear scaffold were disrupted. Our findings suggest that a dynamic protein assembly at the nuclear envelope helps coordinate neuronal activity with gene regulation. Understanding this mechanism provides new insight into how brain cells adapt to activity and may be relevant for neurological disorders in which gene regulation is impaired.

The epigenome and nuclear architectural mechanisms that regulate neuronal activity-induced transcriptional responses in cortical neurons remain incompletely understood. Previously, we have shown that the chromatin organizer SATB2 and the inner nuclear membrane protein LEMD2 form a chromatin tether at the nuclear lamina, and that activity-induced transcription is impaired in both Satb2 and Lemd2 loss-of-function models. Interaction of SATB2 and LEMD2 with subunits of the ESCRT-III complex indicates that the ESCRT-III complex could serve as an activity-dependent, dynamic component of this tether. Here, we study the activity-dependent subcellular localization and function of the ESCRT-III components CHMP7 and CHMP4B in primary cortical neurons. We find that increased neuronal activity correlates with the accumulation of co-localized CHMP7 and CHMP4B foci at the nuclear envelope. shRNA-mediated Chmp7 knockdown causes a reduction in the expression of activity-regulated genes and genes with highly specialized functions in synaptic organization and trans-synaptic signaling. Furthermore, the observed similarity in the global transcriptome responses in Satb2, Lemd2, and Chmp7 loss-of-function models points toward a previously unrecognized role of the SATB2–LEMD2–CHMP7 tether in linking chromatin architecture and nuclear envelope plasticity to activity-dependent gene regulation.