The Plant Nuclear Envelope and Its Role in Gene Transcription

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.

Hi-C experiments measure the probability of physical proximity between pairs of chromosomal loci on a genomic scale. We report on several systematic biases that substantially affect the Hi-C experimental procedure, including the distance between restriction sites, the GC content of trimmed ligation junctions and sequence uniqueness. To address these biases, we introduce an integrated probabilistic background model and develop algorithms to estimate its parameters and renormalize Hi-C data. Analysis of corrected human lymphoblast contact maps provides genome-wide evidence for interchromosomal aggregation of active chromatin marks, including DNase-hypersensitive sites and transcriptionally active foci. We observe extensive long-range (up to 400 kb) cis interactions at active promoters and derive asymmetric contact profiles next to transcription start sites and CTCF binding sites. Clusters of interacting chromosomal domains suggest physical separation of centromere-proximal and centromere-distal regions. These results provide a computational basis for the inference of chromosomal architectures from Hi-C experiments.

The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL). This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome-lamina interactions occur through more than 1,300 sharply defined large domains 0.1-10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.