Cohesin: a critical chromatin organizer in mammalian gene regulation

Abstract

Cohesins are evolutionarily conserved essential multi-protein complexes that are important for higher-order chromatin organization. They play pivotal roles in the maintenance of genome integrity through mitotic chromosome regulation, DNA repair and replication, as well as gene regulation critical for proper development and cellular differentiation. In this review, we will discuss the multifaceted functions of mammalian cohesins and their apparent functional hierarchy in the cell, with particular focus on their actions in gene regulation and their relevance to human developmental disorders.

Fig. 1. Human cohesin

A. Human cohesin complex. B. Proposed models for chromatin trapping (cohesion) by cohesin. C. Structure of an SMC family protein.

Fig. 2. Factors involved in cohesin recruitment to specific genomic regions

A. Binding of RNA polymerase II, Mediator, and sequence-specific transcription factors (TFs), such as ERα, correlates with cohesin binding. B. Pre-replication complex (pre-RC), including the MCM complex, and cohesin binding to replication origins. C. ATP-dependent chromatin remodeling complex hSNF2h binds to cohesin and recruits it to a type of Alu repeat sequence in human cells. D. CTCF-dependent recruitment of cohesin to the insulator/boundary elements containing CTCF consensus binding sites. Additional factors, such as p68/SRA and ATRX, may dictate their binding selectivity. E. CTCF-independent cohesin recruitment to heterochromatic repeat sequences carrying histone H3K9me3 and HP1. At the pericentromeric heterochromatin in S. pombe, HP1 recruits cohesin. At the D4Z4 subtelomeric repeat regions in human cells, cohesin and HP1γ are co-recruited.

Fig. 3

Different types of chromatin looping mediated by cohesin. A. Between insulator/boundary elements. B. Between distal enhancer and promoter regions. C. Between heterochromatic regions (C is hypothetical).

Fig.4

Multiple functions of cohesin in the cell and functional hierarchy. Four major areas of cohesin functions and examples of factors that recruit cohesin to specific sites are listed. Mitotic functions appear to be the least dose-sensitive and most essential, while other interphase functions, such as DNA repair and gene regulation, are more dose-sensitive. Further analysis is needed to determine whether there are significant hierarchical differences among the three non-mitotic functions. TFs: transcription factors.