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May 15, 2009 (Vol. 29, No. 10)

Decoding Cell Communication

Understanding the Functions and Mechanisms of Every Aspect of the Cell Nucleus Now Viewed as Critical

  • Chromosome Crosstalk

    Click Image To Enlarge +
    SATB1 changes chromatin organization and gene expression in breast cancer cells to induce metastasis.

    The architectural organization of the nucleus is poorly understood. However, some active genes are repartitioned from the interior to the periphery of nuclear territories. “A number of studies have shown that there are interchromosomal interactions that provide a novel control mechanism to regulate gene expression,” noted Xiang-Dong Fu, professor, medicine/cellular and molecular medicine, University of California at San Diego (UCSD).

    “New and intriguing questions have emerged from the recent genome-wide analyses of DNA binding sites for transcription factors,” explained Dr. Fu. “We see that there can be numerous remote chromosomal binding sites that communicate with their putative target genes by long-distance intrachromosomal and likely interchromosomal interactions.”

    Dr. Fu and his collaborator, Michael G. Rosenfeld, M.D., an investigator for the Howard Hughes Medical Institute at UCSD, are working to define how such interactions take place. Their studies target genes regulated by nuclear receptors such as the estrogen receptor. “Our groups found 17β-estradiol(E2)-induced interactions between gene loci located in different chromosomes, in particular the TFF1 gene on chromosome 21 and the GREB1 gene on chromosome 2,” Dr. Fu reports.

    Using fluorescence in situ hybridization, Drs. Fu and Rosenfeld found that these interchromosomal interactions appear to be mediated by a nuclear motor system. Dr. Fu added, “this is still poorly understood at this point, but it’s important to note that these gene-gene interactions are closely correlated with enhanced gene expression in response to hormones.”

    Drs. Fu and Rosenfeld also determined that the interchromosomal interactions occurred in hubs called interchromatin granules. “These granules, also called nuclear speckles, are enriched with several key transcriptional elongation factors, chromatin remodeling complexes, and essentially all factors needed for pre-mRNA splicing.”

    These findings underscore the ability of chromosomes to move to and interact at these common hubs, Dr. Fu noted. “For hormone-induced genes, such interchromosomal interactions in the interchromatin granules may play an important role to coordinate and enhance regulated gene expression by allowing efficient coupling of transcriptional initiation, elongation, and RNA-processing events.”

  • Location, Location, Location

    Where a gene is positioned (even in nuclear real estate) can have major ramifications on its activity. The role of the spatial organization of chromatin within the nucleus has been debated for years. But new research has begun to shed light on the subject, according to Jason Brickner, Ph.D., assistant professor, department of biochemistry, molecular biology and cell biology, Northwestern University.

    “When many genes are activated, they relocalize from the nuclear periphery, where they probably associate with the nuclear lamina, to the nuclear interior,” he said. “We are also seeing that a number of genes are specifically targeted to the periphery when they are activated. Surprisingly, if these genes are then turned off, they can remain at the periphery through several cell divisions and possess a memory of the previous activation.”

    Dr. Brickner, who uses yeast as a model system, said such recruited genes can subsequently become more rapidly reactivated when the need arises. “We found that a number of inducible yeast genes are stably targeted to and remain at the nuclear periphery after they have been repressed again. For example, retention of the GAL1 gene (that encodes the galactokinase gene) lasts more than seven generations. While it is at the periphery, it can be reactivated more rapidly than the naïve state of the gene. This type of transcriptional memory requires both chromatin-remodeling factors and the histone variant H2A.Z. So, peripheral localization might represent a novel epigenetic mechanism for transcriptional control.”

    The mechanism for this peripheral association relies on interactions between the nuclear pore complexes and either mRNA or DNA sequences, Dr. Brickner noted. “It’s possible that the genome may encode for its own spatial organization.”

    Some intriguing and important questions remain. For example, how are cytoplasmic factors, chromatin remodeling, and gene localization coordinated to mark a promoter for rapid reactivation? How many genes use this type of transcriptional memory? Finally, what other organisms utilize this system? Dr. Brickner said “one of the most exciting possibilities is that metazoan cells might use this type of regulation. If so, this could provide a means by which environmental factors or physiological signals affect gene expression long after a stimulus is encountered. Although it’s a fantasy now, in the future we may be able to use such knowledge to therapeutically manipulate transcription.”

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