# Runx2 downregulates Lpl expression through super-silencer formation to alter lipid metabolism in Zhu Schwann cells after nerve injury

## TL;DR

This study reveals how Runx2 changes lipid metabolism in Schwann cells after nerve injury by forming a super-silencer that suppresses Lpl gene expression.

## Contribution

The first super-silencer landscape in Schwann cells with Runx2 overexpression is identified, linking it to lipid metabolism regulation.

## Key findings

- Runx2 forms a super-silencer in the Lpl gene region, downregulating its expression in Schwann cells.
- Lipid metabolism is disrupted in Runx2-overexpressing Schwann cells following nerve injury.
- Modified molecular markers for repair-type Schwann cells are described.

## Abstract

Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. Nonetheless, the regulatory mechanisms that govern its epigenetic regulation are not yet fully elucidated.

To facilitate this investigation, an adenovirus for the overexpression of Runx2 was constructed. Healthy adult Sprague–Dawley rats, weighing between 100 and 150 g and irrespective of sex, were randomly selected for the study. After establishing a model of sciatic nerve crush injury, tissue samples were harvested for histological analysis at both 4 and 7 days post-injury. In vitro, an Runx2-overexpressing SC line was established. Thorough analysis of transcriptome data, coupled with CUT&Tag sequencing of histones and transcription factors in SCs following Runx2 overexpression, was conducted. Additionally, single-cell RNA sequencing data from GSE216665 were incorporated to elucidate the mechanistic role of Runx2. The findings were subsequently validated through dual-luciferase assays.

Following nerve crush injury, Runx2-positive SCs were identified at the injury site. Through comprehensive multiomics analysis, we discovered that lipid metabolism was disrupted in Runx2-overexpressing SCs. Further investigation established a detailed super-silencer landscape in these cells, revealing that elevated Runx2 levels form a super-silencer within the transcriptional regulatory region of the Lpl gene, thereby downregulating Lpl expression.

Runx2 can modulate the biological behavior of SCs by forming super-silencers that interfere with the expression of lipid metabolism genes, such as Lpl, thereby altering the metabolic capacity of SCs.

The online version contains supplementary material available at 10.1186/s11658-025-00796-6.

We identified the first “super-silencer” landscape in SCs with Runx2 overexpression (Zhu1 SCs).We validated that Runx2 suppresses Lpl expression in SCs through the formation of super-silencer sequences, regulating lipid metabolism in SCs during early peripheral nerve injury. We describe modified molecular markers for repair-type SCs.

We identified the first “super-silencer” landscape in SCs with Runx2 overexpression (Zhu1 SCs).

We validated that Runx2 suppresses Lpl expression in SCs through the formation of super-silencer sequences, regulating lipid metabolism in SCs during early peripheral nerve injury.

We describe modified molecular markers for repair-type SCs.

The online version contains supplementary material available at 10.1186/s11658-025-00796-6.