# LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis

## TL;DR

This paper shows that LBR and LAP2 proteins help anchor heterochromatin to the nuclear envelope, and their absence disrupts genome organization and gene regulation.

## Contribution

The study identifies LBR and LAP2 as key proteins mediating heterochromatin tethering to the nuclear periphery in mammalian cells.

## Key findings

- Loss of LBR and LAP2 causes heterochromatin to detach from the nuclear envelope and move to the nuclear interior.
- Long-term absence of LBR and LAP2 leads to changes in 3D chromatin organization and reduced repressive epigenetic marks like H3K27me3.
- These changes trigger gene expression deregulation, antiviral immunity activation, and defects in cell fate determination.

## Abstract

In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tethering to the NE; however, its importance for cellular homeostasis is largely unexplored. One tether is constituted by the lamin B receptor (LBR) in mammals, but the enigmatic nature of other redundant tethers has hampered functional analyses. Here we demonstrate that downregulation of abundant, ubiquitous NE proteins can induce the global detachment of heterochromatin from the NE and its repositioning to the nuclear interior. We identify LBR and lamina-associated polypeptide 2 (LAP2) as key factors for peripheral heterochromatin positioning in differentiated and pluripotent mammalian cells. Their long-term loss leads to changes in three-dimensional chromatin organization and a reduction in repressive epigenetic marks, especially H3K27me3. These changes are associated with massive deregulation of gene expression, activation of antiviral innate immunity, and defects in cell fate determination.

Lewis et al. identify lamin B receptor (LBR) and lamina-associated polypeptide 2 (LAP2) as major factors that tether heterochromatin to the envelope. Deletion of these proteins causes changes in 3D genome organization, gene expression and cell fate determination.