Chromatin-associated proteins

The DNA content of a cell is packaged into a proteinaceous stuctures called chromosomes. There are many different types of proteins known to be associated with chromosomes. Although some of the more abundant ones, such as the histones and high mobility group proteins have been studied for many decades, others have been more recently reported and there is no doubt a substantial number remaining to be discovered. The way DNA is packaged governs its access to and interaction with the machinery of the nucleus, so as well as playing a structural role, chomosomal proteins may be involved in many basic nuclear functions such as gene transcription or silencing, DNA replication and repair, chromosomal segregation and nuclear organization.

Types of Chromatin-associated Proteins

The proteins most intimately associated with DNA are the histones, small basic proteins which when associated with DNA form the nucleosome. The 10 nm nucleosomal DNA fibre undergoes higher order packaging to give chromosomes. Histones can be modified by phosphorylation, acetylation and methylation which can affect the compaction of the chromatin fibre and/or the proteins that then associate with the chromatin template. The high mobility group (HMG) proteins are also small, basic chromosomal proteins that bind DNA via motifs as HMG boxes and A-T hooks. Although they do not bind to specific DNA motifs, they may show preference for certain regions of DNA. For example, A-T hooks bind preferentially to A-T-rich DNA. HMG proteins are usually described as architectural transcription factors as they are thought to facilitate transcription (or other chromosomal functions) by bending and deforming the DNA/chromatin.

Eukaryotic chromosomes are composed of two types of chromatin as distinguished by the light or electron microscope. Euchromatin is lighter staining, gene-rich and can be transcriptionally active, while heterchromatin stains darkly, is gene poor and transcriptionally repressed. Other known components of the chromosomes came out of screens for proteins in Drosophila and yeast that modify position effect variegation (PEV), the transcriptional silencing observed when euchromatic genes are placed adjacent with heterochromatin. Supressors of variegation (Su[var]s) are proteins that favour heterochromatin formation and include structural components such as Su(var) 2-5 (HP1) or components with enzymatic activity such as Su(var) 3-9 (Clr1), which methylates histone H3 at lysine 9 to which HP1 binds. Enhancers of variegation (En[var]s) antagonize heterochromatin formation. Proteins that silence and/or maintain the silenced state of genes in euchromatic sites were also discovered from studies of homeotic transformation in Drososophila. Polycomb and polycomb group (PcG) proteins cause the repression of homeotic genes in specific body segments and then maintain the silent state through development, while trithorax and trithorax group (TrxG) proteins antagonize gene silencing to allow the locus to be expressed. While these proteins have been found associated with specific regions of chromatin, it has been suggested and now in some cases confirmed that similar mechanisms act to activate or repress many types of euchromatic genes. For example silencing of the Rb gene p53 is HP1 dependent (Nielsen et al., 2001) [1].

Mammalian homologues of the Su(var)/En(var) and PcG/TrxG proteins have been found, although there can be additional layers of complexity. For example, there are three mammalian HP1s, HP1a, b and g, which localize to different chromosomal compartments; HP1a is mostly heterochromatic, HP1b is both euchromatic and heterochromatic and HP1g is mainly found in euchromatin.

Another major class of proteins that interact with chromosomes are the chromatin remodelling proteins. These proteins utilize ATP to move nucleosomes along the DNA template. Swi/Snf proteins. ACF, ATRX etc.

Chromosomal Proteins and Disease

A number of chromosomal proteins have been implicated in human disease and cancer. Deletion of HMGA1, a HMG protein in the mouse results in a pygmy phenotype, however in human this gene loci is often found to be involved in translocations, where it results in lipomas. MeCP2 is a protein that binds methylated DNA (predominantly found at heterochromatin) and has been recently identified as the gene mutated in Retts syndrome, which is characterized by mental retardation, motor defects etc. Mutations in the swi/snf protein ATRX are responsible for ATRX syndrome which also results in mental retardation, and in addition a-thalassemia, abnormal facial features and sexual defects, presumably due to abnormal transcription of a number of target gene loci for this global transcriptional regulator. It also results in abnormal methylation of certain gene loci. Another swi/snf protein INK4 is mutated in cancers.

Gene-trapping Chromosomal Proteins

Gene screens have been a rich source of the chromosomal proteins identified to this day and due to the size of mammalian chromosomes, a visual gene-trap screen allow the discovery of more chromosomal components. From a gene-trap perspective, a number of types of chromosomal proteins can be identified. Proteins may localize all over chromosomes, or be restricted to either euchromatin of heterochromatin. Proteins may also interact with chromosomes at specific times of the cell cycle. For example, many kinetochore components are located on chromosomes at the kinetochore only for mitosis. Some proteins are chromosomal throughout the cell cycle, while some proteins may be associated with chromosomal arms only during division, and others are found on interphase chromatin in a subset of cells, suggesting they interact with chromosomes at a specific time of the cell cycle or state of differentiation.


  1. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O'Carroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T. (2001) Rb targets histone H3 methylation and HP1 to promoters. Nature 412:561-565