Atlas of Genetics and Cytogenetics in Oncology and Haematology

Patricia Ridgway1,3, Christele Maison2,3 and Genevieve Almouzni2 1. Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia. 2. UMR 218 du CNRS, Institut Curie, 26 rue d'ULM, 75248 Paris Cedex 05, France. 3. equal contribution. May 2002 Introduction In eukaryotic cells the genetic material is organized into a complex structure composed of DNA and proteins and localized in a specialized compartment, the nucleus. This structure, detected with basic dyes, was called chromatin (from the Greek "khroma" meaning coloured and "soma" meaning body) at the end of the 19 centruy [Flemming, 1882 #24]. Close to two meters of DNA in each cell must be assembled into a small nucleus of some in diameter. Despite this enormous degree of compaction, DNA must be rapidly accessible to permit its interaction with protein machineries that regulate the functions of chromatin: replication, repair and recombination. The dynamic organization of chromatin structure thereby influences, potentially, all functions of the genome. The fundamental unit of chromatin, termed the nucleosome, is composed of DNA and histone proteins. This structure provides the first level of compaction of DNA into the nucleus. Nucleosomes are regularly spaced along the genome to form a nucleofilament which can adopt higher levels of compaction (Figures 1 and 3), ultimately resulting in the highly condensed metaphase chromosome. The combined approaches of cell biology and genetic studies have led to the discovery that within an interphase nucleus chromatin is organized into functional territories [Cockell, 1999 #2]. Historically, based on microscopic observations, chromatin has been divided into two distinct domains, heterochromatin and euchromatin. Heterochromatin was defined as a structure that does not alter in its condensation throughout the cell cycle whereas euchromatin is decondensed during interphase [Heitz, 1928 #1]. Typically in a cell, heterochromatin is localized principally on the periphery of the nucleus and euchromatin in the interior of the nucleoplasm. We can distinguish constitutive heterochromatin, containing few genes and formed principally of repetitive sequences located in large regions coincident with centromeres and telomeres, from facultative heterochromatin composed of transcriptionally active regions that can adopt the structural and functional characteristics of heterochromatin, such as the inactive X chromosome of mammals [Lyon, 1999 #25] [Avner, 2001 #26]. In this review we will define the components of chromatin and outline the different levels of its organization from the nucleosome to domains in the nucleus. We will discuss how variation in the basic constituents of chromatin can impact on its activity and how stimulatory factors play a critical role in imparting diversity to this dynamic