Mechanisms of cohesin-mediated gene regulation and lessons learned from cohesinopathies

Abstract

Cohesins are conserved and essential Structural Maintenance of Chromosomes (SMC) protein-containing complexes that physically interact with chromatin and modulate higher-order chromatin organization. Cohesins mediate sister chromatid cohesion and cellular long-distance chromatin interactions affecting genome maintenance and gene expression. Discoveries of mutations in cohesin's subunits and its regulator proteins in human developmental disorders, so-called "cohesinopathies," reveal crucial roles for cohesins in development and cellular growth and differentiation. In this review, we discuss the latest findings concerning cohesin's functions in higher-order chromatin architecture organization and gene regulation and new insight gained from studies of cohesinopathies. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.

Keywords: Cohesin; Cohesinopathy; Cornelia de Lange Syndrome; NIPBL; Roberts' Syndrome.

Figure 1

Schematic diagrams of cohesin-SA1 and cohesin-SA2.

Figure 2

Regulators of cohesin loading and establishment of sister chromatid cohesion. The cohesin loading factor, NIPBL-MAU2 (Scc2-Scc4), is required for cohesin loading onto chromatin in telophase in mammalian cells. The initial loading of NIPBL-MAU2 is dependent on the pre-replication machinery. In S phase, the establishment of sister chromatid cohesion requires sororin and Pds5A/B as well as the ESCO1/2 (Eco) acetyltransferases that coordinately antagonize the activity of the cohesin destabilizing factor Wapl. ESCO-mediated acetylation of the cohesin subunit SMC3 must be reversed by histone deacetylase HDAC8 in order to refresh and recycle cohesin for the subsequent cell cycle. Mutations associated with the cohesinopathies RBS and CdLS are indicated.

Figure 3

CTCF-dependent and -independent chromatin loop formation at the β-globin locus. Cohesin binds to and mediates the long-distance interactions of CTCF-bound insulator elements flanking the locus as well as between the distal enhancer (Enh) in the locus control region and the adult globin genes (white box with an arrow) [82]. The pink circle represents the presence of various transcription factors involved in globin gene expression, such as EKLF (Klf1), GATA-1, Fog-1, Ldb1, and NF-E2 [, –104, 147]. A white box without an arrow represents the inactive gene, which is not interacting with the enhancer.

Figure 4

Cohesin recruitment to heterochromatin. Blue double-sided arrows indicate the interactions reported. Pink arrows indicate downstream effects. A. Cohesin and HP1γ require each other to bind to the D4Z4 subtelomeric heterochromatin in a SUV39H-mediated H3K9me3-dependent manner [116]. Direct interaction of NIPBL with HP1 may contribute [116, 156]. The light blue arrow indicates co-recruitment of cohesin and HP1γ to D4Z4 [116]. In addition, an SMC homolog, SMCHD1, binds to D4Z4 [215]. Whether this binding is mediated by HBiX1, an HP1-interacting protein, as observed at the inactive X chromosome [198] is currently unclear. SMCHD1 was shown to be important for the maintenance of DNA methylation [214]. Whether it contributes to DNA hypermethylation at D4Z4 has not been determined. B. Cohesin is recruited to pericentromeric heterochromatin via interaction with histone methyltransferase Suv4-20h2, which mediates H4K20me3. Suv4-20h2 localization is dependent on HP1 bound to methylated H3K9 mediated by SUV39h [157]. The relevance of the NIPBL-HP1 interaction [156] to pericentromeric cohesin recruitment is unclear.