Increasing evidence suggests functional compartmentalization of interphase nuclei. This includes preferential interior localization of gene-rich and early replicating chromosome regions versus peripheral localization of gene-poor and late replicating chromosome regions , association of some active genes with nuclear speckles or transcription "factories", and association of transcriptionally repressed genes with heterochromatic regions. Dynamic changes in chromosome compartmentalization imply mechanisms for long-range interphase chromatin movements. However, live cell imaging in mammalian cells has revealed limited chromatin mobility, described as "constrained diffusion". None of these studies, though, have examined a chromosome locus undergoing an inducible repositioning between two different nuclear compartments. Here we demonstrate migration of an interphase chromosome site from the nuclear periphery to the interior 1-2 hr after targeting a transcriptional activator to this site. Spot redistribution is perturbed by specific actin or nuclear myosin I mutants. Extended periods of chromosome immobility are interspersed with several minute periods in which chromosomes move unidirectionally along curvilinear paths oriented roughly perpendicular to the nuclear envelope at velocities of 0.1-0.9 microm/min over distances of 1-5 microm. Our results suggest an active mechanism for fast and directed long-range interphase chromosome movements dependent directly or indirectly on actin/myosin.

The past decade has seen an increasing appreciation for nuclear compartmentalization as an underlying determinant of interphase chromosome nuclear organization. To date, attention has focused primarily on describing differential localization of particular genes or chromosome regions as a function of differentiation, cell cycle position, and/or transcriptional activity. The question of how exactly interphase chromosome compartmentalization is established and in particular how interphase chromosomes might move during changes in nuclear compartmentalization, has received less attention. Here we review what is known concerning chromatin mobility in relationship to physiologically regulated changes in nuclear interphase chromosome organization.

Ethanol consumption induces hepatocellular carcinoma (HCC) cell metastasis by changing the extracellular matrix (ECM). Lysyl oxidase (LOX) catalyzes the cross-linkage of collagen or elastin in the ECM. LOX protein and mRNA overexpression (>21-fold compared with controls, n = 6) was detected in cirrhotic HCC patients with a history of alcoholism. LOX protein expression was induced in HCC cells after long-term treatment with ethanol (10 mM) for 20-40 passages (denoted E20-E40 cells). Pterostilbene (PSB, 1 μM) displayed significant potency to reduce LOX-mediated activity in E40 cells when combined with curcumin and its analogues. The ability of E40 cells to form colonies in soft agar was reduced by both genetic depletion of LOX and by chemical inhibitors of LOX expression. This study suggests that targeting LOX expression with food components such as PSB and curcumin may be a novel strategy to overcome ethanol-induced HCC cell metastasis in liver cancer patients.

A recent paper demonstrates that coregulated genes on different chromosomes show surprisingly high frequencies of colocalization within the nucleus; this complements similar results found previously for genes localized tens of megabases apart on a single chromosome. Colocalization could be related to the earlier observation of active genes associating with foci where RNA polymerase II is concentrated. Nuclear compartmentalization and its study using the 3C methodThe nucleus is still not infrequently perceived as a microscopic test tube, in which activities such as transcription, replication, and recombination are performed on a template of randomly coiled chromatin bathed in a homogeneous nucleoplasm containing soluble enzymes and cofactors. Yet in recent years there has been a growing appreciation that the nucleus is in fact highly organized. In interphase chromosomes, DNA is compacted by varying amounts, from hundreds to thousands of times more compact than simple B-form DNA [1], and the chromosomes form distinct, largely non-overlapping 'territories ' [2] that are non-randomly arranged within the nucleus. As well as chromosome territories, a plethora of other nuclear compartments and bodies have been identified, and many of the cofactors and enzymes mediating the processing of DNA and RNA are enriched in particular compartments or bodies [3]. The functional significance of this considerable nuclear compartmentalization remains unclear given that most nuclear proteins are quite dynamic, equilibrating rapidly between specific compartments and a soluble nucleoplasmic pool. But a 2004 paper [4] that examined the colocalization of active genes on the same chromosome arm fueled speculation about the possible functional significance of nuclear compartmentalization. A new report [5] now ignites interest in nuclear compartmentalization by extending this work to coregulated foci on different chromosomes. Both papers break new ground by combining the recently developed 'chromosome conformation capture' (3C) method -a molecular method for assaying chromosome proximity -with more established fluorescent in situ hybridization (FISH) and immunocytochemistry techniques.The 3C technique provides a powerful tool for dissecting the spatial organization of chromosomes within nuclei [6]. The 3C method identifies DNA sequences that are in close molecular proximity by detecting indirect linkage between them, mediated through formaldehyde-induced DNA-protein and protein-protein cross-links. Following treatment of intact cells with formaldehyde, isolated DNA-protein complexes are subjected to restriction-enzyme digestion. DNA fragments held together via cross-linked DNA-protein complexes have a higher probability than soluble DNA fragments of being ligated together at low DNA concentrations. Reversal of the formaldehyde cross-links is followed by detection using PCR of the relative cross-linking frequency of two DNA fragments, which is assumed to be proportional to their spatial proximity in the nucleus. Association of link...