Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression

Abstract

In metazoan cell nuclei, hundreds of large chromatin domains are in close contact with the nuclear lamina. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression. Here, we discuss the properties of LADs, the molecular mechanisms that determine their association with the nuclear lamina, their dynamic links with other nuclear compartments, and their proposed roles in gene regulation.

Keywords: LADs; chromosome architecture; gene repression; heterochromatin; lamina-associated domains; nuclear architecture.

Figure 1. NL-associated heterochromatin

A. Electron micrograph of part of a mouse cell nucleus. Densely stained chromatin is closely associated with the NL, but is also present around nucleoli and in patches elsewhere in the nucleus. Image provided by Kenneth M. Bart. B. Labeling of DNA–NL contacts by co-expression of Dam-Lamin B1 and a GFP-tagged ^m6A-tracer protein that binds to adenine-methylated DNA (green) in a cultured human cell. Image by Jop Kind. A single confocal section is shown. Lamin B1 is shown in red. C. Cartoon model illustrating how a chromosome (blue) is associated with the NL through multiple LADs that jointly form a heterochromatin layer (green). Only one chromosome is depicted. D. Schematic representation of a DamID track of interactions with the NL along part of a mammalian chromosome, illustrating the size range, relative sharply defined edges, and broad distribution of LADs. LADs are highlighted in green, inter-LAD regions in blue.

Figure 2. Dynamic compartmentalization of chromosomal domains

A. Besides anchoring of LADs (green) to the NL, other regions (blue) may be tethered to nuclear structures that are permissive for transcription (orange), such as transcription factories (tf) or splicing factor speckles (speckles). B. Some LADs (semi-transparent green) contact the NL erratically (i.e., in a subset of cells) and may become transcriptionally active when associated with a permissive compartment (semi-transparent blue). C. Some LADs are apparently stochastically distributed between the NL, nucleoli and pericentromeric heterochromatin (ph), which are all repressive environments.

Figure 3. LADs compared to domains as identified by Hi-C

Comparison of a NL contact frequency profile and Hi-C data in human KBM7 cells (see Data Analysis). Note the remarkably strong similarity of NL contact frequencies to the compartment A/B profile, and the partial similarity to TAD structure.