April 19 2010

Impact of nuclear chromatin localization on differentiation and transformation

Spatial arrangement of chromatin within the nucleus plays a role in the control of genome function, including transcription, DNA replication and repair. In addition, changes in chromatin organization in the nucleus have been used for decades as clinical markers for oncogenic transformation. However, little was understood about the processes that drive these nuclear events. Two publications from Susan Gassers research group at the FMI shed light on the molecular processes that govern nuclear chromatin localization and their role in differentiation and controlled gene expression.

The spatial dynamics of tissue specific promoters during C. elegans development
Using the genetically amenable model organism C. elegans, a small worm commonly found on rotting fruits, FMI scientists have shown that the driving force for gene localization is encoded in the DNA sequence of promoters. Cell type-specific developmentally regulated promoters direct genes either to the nuclear interior when they are active or towards the compacted chromatin at the nuclear periphery when inactive. In muscle differentiation this is controlled by the presence of a "master regulatory" transcription factor called Hlh-1 (MyoD in mammals). Specific localization is not seen in committed embryonic cells nor for housekeeping genes. The authors find a dramatic increase in nuclear compartmentalization during the course of development and cell differentiation. This study opens the way to genetic analysis of nuclear organization and will allow the analysis of human diseases linked to nuclear function using worms as models.
» Publication in Genes & Development

Influence of actin-related protein, Arp6, on nuclear organization
In collaboration with a laboratory from Tohoku University, the Gasser laboratory at FMI examined the role of a highly conserved, nuclear localized actin-related protein, Arp6, in nuclear organization. They could show that the budding yeast Arp6 contributes to the anchorage of chromatin domains to the nuclear pore complex. One set of genes anchored through Arp6 are a subset of ribosomal protein (RP) genes, which themselves respond to changes in cell metabolism to control protein synthesis and cell growth. The loss of RP gene positioning at pores by loss of Arp6 correlates with an up-regulation in their expression. These observations provide first evidence for the involvement of an actin-related protein in long-range chromatin organization in the interphase nucleus. It identifies a new player involved in nuclear organization that has similarities to the major cytoplasmic structural protein, actin.
» Publication in PLOS Genetics

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