LADs

Lamina-associated domains (LADs) are large genomic regions that interact with the nuclear lamina at the inner surface of the nuclear envelope. Located predominantly at the nuclear periphery, LADs are generally gene-poor and show reduced transcriptional activity, contributing to the spatial organization of the genome by anchoring chromatin to the lamina.

LADs were first mapped in mammalian cells using DamID, a method in which a DNA adenine methyltransferase is fused to a lamina protein to mark nearby DNA. Subsequent genome-wide maps have been generated using Lamin B1 or Lamin A/C chromatin immunoprecipitation. These approaches reveal a landscape of lamina-associated chromatin that spans large genomic blocks.

LADs vary in their stability and cell-type specificity. Constitutive LADs (cLADs) are found across many cell types, while facultative LADs (fLADs) are cell-type specific and can change during development or differentiation. Inter-LADs are regions that do not associate with the lamina. LADs are typically megabase-scale, enriched for repressive chromatin features, late replication timing, and low gene density, and often have AT-rich DNA. Genes within LADs tend to be silenced or expressed at low levels, and repositioning in and out of LADs can accompany changes in gene expression.

The lamina-genome association contributes to higher-order genome organization, often in coordination with topologically associating domains (TADs) and other chromatin features. Alterations in LAD organization have been linked to aging and disease; for example, mutations in LMNA (lamin A/C) and other lamina components can disrupt lamin–chromatin interactions and genome positioning, contributing to muscular dystrophies, lipodystrophies, and progeroid syndromes.

Common methods to study LADs include DamID and Lamin B1 or Lamin A/C ChIP, each with its own strengths and limitations for inferring lamina proximity and chromatin state.