Choreography of lamina-associated domains: structure meets dynamics

Abstract

Lamina-associated domains are large regions of heterochromatin positioned at the nuclear periphery. These domains have been implicated in gene repression, especially in the context of development. In mammals, LAD organization is dependent on nuclear lamins, inner nuclear membrane proteins, and chromatin state. In addition, chromatin readers and modifier proteins have been implicated in this organization, potentially serving as molecular tethers that interact with both nuclear envelope proteins and chromatin. More recent studies have focused on teasing apart the rules that govern dynamic LAD organization and how LAD organization, in turn, relates to gene regulation and overall 3D genome organization. This review highlights recent studies in mammalian cells uncovering factors that instruct the choreography of LAD organization, re-organization, and dynamics at the nuclear lamina, including LAD dynamics in interphase and through mitotic exit, when LAD organization is re-established, as well as intra-LAD subdomain variations.

Keywords: 3D genome organization; CTCF; Hi-C; cell cycle; chromatin; heterochromatin; inner nuclear membrane; lamina-associated domains; lamins; nuclear lamina.

Figure 1:

Schematic of LAD and genome organization Lamina-Associated Domains (LADs, red) are regions of heterochromatin that associate with the nuclear lamina (green shading). LADs are part of the B-compartment as determined by Hi-C studies. non-LAD active chromatin (A-compartment, cyan) is organized into active topologically associating domains (active TADs) and sub-TADs through domain anchors CTCF, cohesin, and other factors. TADs can be further folded and looped via intra-TAD regulatory interactions (e.g. enhancer: promoter pairs, CTCF). While LADs are also bordered by CTCF and cohesin, LADs do not form loops like active TADs, nor do they form the same sub-domain loop structures. Indeed, LADs are generally devoid of both CTCF and cohesin except at border regions and in regions that ‘dip’ or loop away. These border regions (transitions) are also enriched for H3K27me3. While LADs can be defined by their proximity to the nuclear lamina and some shared characteristics, LADs display great inter- and intra-LAD heterogeneity. cLADs (constitutive LADs) tend to be gene-poor and show the most consistent and persistent localization to the lamina. Gene-rich LADs comprise the facultative LAD (fLAD) population and can display, depending on cell type, more dynamic interactions with the lamina (depicted as a wavy LAD). In some cell types, these fLADs move away from the lamina and are expressed (and thereforeno longer a LAD). Regions within LADs can also dip away locally (<20Kb regions) to allow expression from a transcription start site (TSS) of a gene, usually with aborted transcripts, or to engage with the A-compartment (e.g. an enhancer looping out). Note that heterochromatin is not restricted to the lamina including some centromeric, telomeric, and nucleolar regions, but can also be found “trapped” in the midst of the A-compartment (gray). While LADs can comprise 30–50% of the genome of a given cell type, not all of those lamina interactions are found in every cell within a population. At least for some cultured cell models, in individual cells only about 1/3 of LADs defined in the cell population actually reside at the lamina at any given time and many of these are stochastically repositioned to intranuclear sites (including perinucleolar regions). Two transition regions are shown as “zoomed in views” to incorporate CTCF and cohesin. Please note that this is an artistic rendering of LAD and genome organization. See text for more details and references. Adapted from [18].

Figure 2:

The Growing list of “Middlemen” LADs are enriched for repressive heterochromatin marks and localization to the lamina is dependent on H3K9me2/3 and, to some degree, H3K27me3. Shown in this schematic are proteins found to interact with either chromatin or chromatin modifiers/interactors as well as the nuclear lamina–i.e. these proteins serve as molecular bridge or tether. Among these tethers ZKSCAN3, PRDM16, MECP2, BANF, AHCTF1, and PRR14 (green), some of which interact with lamin B receptor (LBR) or LEM domain proteins as indicated. Chromatin interactors are shown in pink. Of special note, both TRIM28 (KAP1) and HP1α have also been shown to interact with the lamina or INM proteins but are treated in this figure as indirect (and chromatin-centric) given their repeated appearance in multiple complexes. See text for details and references. Adapted from [91].