Condensin and cohesin complexity: the expanding repertoire of functions

Abstract

Condensin and cohesin complexes act in diverse nuclear processes in addition to their widely known roles in chromosome compaction and sister chromatid cohesion. Recent work has elucidated the contribution of condensin and cohesin to interphase genome organization, control of gene expression, metazoan development and meiosis. Despite these wide-ranging functions, several themes have come to light: both complexes establish higher-order chromosome structure by inhibiting or promoting interactions between distant genomic regions, both complexes influence the chromosomal association of other proteins, and both complexes achieve functional specialization by swapping homologous subunits. Emerging data are expanding the range of processes in which condensin and cohesin are known to participate and are enhancing our knowledge of how chromosome architecture is regulated to influence numerous cellular functions.

Figure 1. Dosage compensation in Caenorhabditis elegans

a | In Caenorhabditis elegans, a regulatory hierarchy controls both dosage compensation and sex determination in response to the primary sex determination signal, the X:A (autosome) ratio. Low ratios (for example, 1X:2A) activate the master switch gene XO lethal 1 (xol-1), which promotes male sexual development and inhibits dosage compensation^,. High ratios (for example, 2X:2A) silence xol-1, thereby promoting hermaphrodite sexual development and the activation of dosage compensation. xol-1 repression permits the XX-specific gene sex and dosage compensation 2 (sdc-2) to be active. SDC-2 acts with SDC-3 and DPY-30 to trigger assembly of a dosage compensation complex (DCC) onto multiple sites along X chromosomes to bring about a 50% reduction in gene expression. SDC-2 acts with SDC-1 and SDC-3 to induce hermaphrodite development by binding to the autosomal male-fate-promoting gene hermaphrodization 1 (her-1) to repress its expression ~20-fold. b | The DCC (shown in the figure as condensin I^DC) consists of five condensin-like components and at least five additional factors, which confer X- and sex-specificity^,. c | DCC-binding sites have been mapped by chromatin immunoprecipitation followed by microarray analysis (ChIP–chip), as shown here for mapping of SDC-3 binding on the X chromosome, and have been classified into two categories by functional analysis: recruitment elements on X (rex) sites and dependent on X (dox) sites. d | Confocal images of intestinal cell nuclei stained with the DNA dye 4,6-diamidino-2-phenylindole (DAPI) (blue), antibodies to the DCC subunit DPY-27 (red) and a fluorescence in situ hybridization probe that labels extrachromosomal arrays, which contain multiple copies of rex or dox sites (green). The rex sites robustly bind the complex when they are detached from X and are present in multiple copies on extrachromosomal arrays or integrated onto autosomes at low copy numbers. dox sites fail to bind the DCC when detached and must therefore depend on a broader X chromosomal context for their ability to associate with the DCC. e | A 12-bp consensus motif (motif enriched on X (MEX)) is enriched in rex sites relative to dox sites and on X chromosomes relative to autosomes. Mutations in the motif disrupt the ability of rex sites to recruit the DCC. Panels c and e are modified, with permission, from REF. 25 © (2008) Cold Spring Harbor Press.

Figure 2. Cohesin function in gene expression

a | Cell-cycle-dependent control of 3'-end processing in fission yeast. During the G1 phase of the cell cycle, read-through transcription from convergently transcribed gene pairs generates overlapping transcripts, which are cleaved to small interfering RNAs (siRNAs) by Dicer to induce localized transient heterochromatin formation (represented in the figure by nucleosomes marked with histone 3 lysine 9 methylation (H3K9me)) specifically during G1/S phase. Cohesin is then recruited to these sites through an interaction with the heterochromatin-associated protein Swi6. During G2, cohesin promotes the use of upstream transcriptional termination sites, preventing read-through transcription and further dsRNA formation. Cohesin removal during mitosis re-establishes read-through transcription and the cycle is repeated. b | Allele-specific chromatin looping at a human imprinted locus. H19 and insulin-like growth factor 2 (IGF2) are linked imprinted genes that are expressed from only the maternal (above chromosome) and paternal (below chromosome) alleles, respectively. The imprinting control region (ICR) situated between the two genes coordinates allele-specific expression patterns and acquires allele-specific CpG methylation during male and female gametogenesis, a pattern that is maintained in somatic tissues following fertilization. Allele-specific chromatin immunoprecipitation (ChIP) assays identified biallelic (maternal and paternal) binding of CCCTC-binding factor (CTCF) and cohesin to a region (CTCF AD1) adjacent to the IGF2 promoters, to the central conserved domain (CCD) and to a region (CTCF DS) downstream of the IGF2 enhancers. Chromosome conformation capture (3C) experiments identified maternal-specific and paternal-specific physical interactions among these sites. On the maternal allele, CTCF and cohesin bind to the unmethylated ICR, coincident with the establishment of a DNA loop containing the H19 gene and downstream IGF2 enhancers. This loop is thought to sequester the enhancers from activating IGF2. On the paternal allele, CpG methylation at the ICR prevents CTCF and cohesin binding, leading to a distinct loop structure that allows IGF2 to interact with the enhancers, thereby activating expression. For clarity, interactions between CTCF/cohesin-binding sites that occur at comparable levels on both alleles are not shown in the left panel. The right panel depicts a schematic model for allele-specific chromosome conformation at this locus, based on 3C data from REF. 15. For simplicity, a single cohesin complex represents all cohesin and CTCF binding in the right panel, although the number of distinct complexes bound to these sites is not known.