Oratoria El Medio Ambiente

Review articles

Concepts in nuclear architecture
Tom Misteli
Summary Genomes are defined by their primary sequence. The functional properties of genomes, however, are determined by far more complex mechanisms and depend on multiple layers of regulatory control processes. A key emerging contributor to genome function is the architectural organization of the cell nucleus. The spatial andtemporal behavior of genomes and their regulatory proteins are now being recognized as important, yet still poorly understood, control mechanisms in genome function. Combined cell biological, molecular and computational analysis of architectural aspects of genome function has added a further dimension to the investigation of some of the most fundamental cellular processes including transcription andmaintenance of genome integrity. The complete elucidation of the contribution that nuclear architecture makes to gene expression will be required to fully understand physiological processes such as differentiation, development and disease at the cellular level. Here I give an overview of some of the emerging concepts in the study of in vivo genome organization and function. BioEssays 27:477–487,2005. Published 2005 Wiley Periodicals, Inc.{ Introduction Genomes function in the context of nuclear architecture. Recent work has lead to the realization that the mammalian cell nucleus is a spatially and functionally compartmentalized organelle containing numerous proteinaceous nuclear bodies as well as non-randomly positioned genome domains. The spatial and temporal aspects of genome organizationhave likely functional consequences as indicated by the fact that changes in nuclear architecture are amongst the most dramatic hallmarks of development and differentiation processes and defects in architectural elements of the cell nucleus are now known to be responsible for several human diseases. The key question of how genome function is integrated into the architectural framework of the cellnucleus and how structural elements of the nucleus affect nuclear processes including gene expression, DNA repair and genome stability are critical to our understanding of genome function. The intense study of nuclear architecture has lead to the emergence of several general concepts, many of them surprising and provocative. I give here a brief overview of the most central ones. I deliberately donot discuss any one concept in detail, but aim to provide a broad overview of the general ideas that form the framework for our understanding of nuclear function. For a detailed discourse of each topic, I refer the reader to several excellent recent review articles. The concept of nuclear compartments A central feature of the mammalian cell nucleus is its morphological and functionalheterogeneity generated by the presence of distinct nuclear compartments.(1,2) A nuclear compartment is defined as a macroscopic region within the nucleus that is morphologically and/or functionally distinct from its surrounding. Compartments are generally proteinaceous nuclear bodies or chromatin domains (Fig. 1).

Proteinaceous nuclear ‘bodies’
Nuclear compartments are membraneless suborganellescharacterized by a distinct set of resident proteins. The most prominent nuclear bodies include the nucleolus, which is the site of transcription and processing of ribosomal RNA, the splicing factor compartments, which act as a storage/ assembly site for spliceosomal components, the Cajal body, which is the proposed site of snRNP assembly and the PML body, which is of unknown function.(1) In addition tothese structures, many additional nuclear bodies characterized by the presence of one or multiple nuclear proteins have been described in the literature.(2) The function of many of these bodies remains elusive. However, conceptually at least three models must be considered for the function of a nuclear body. First, the body may not be of functional relevance. The observed morphological bodies may...