How many roads lead to cohesinopathies?

Abstract

Genetic mapping studies reveal that mutations in cohesion pathways are responsible for multispectrum developmental abnormalities termed cohesinopathies. These include Roberts syndrome (RBS), Cornelia de Lange Syndrome (CdLS), and Warsaw Breakage Syndrome (WABS). The cohesinopathies are characterized by overlapping phenotypes ranging from craniofacial deformities, limb defects, and mental retardation. Though these syndromes share a similar suite of phenotypes and arise due to mutations in a common cohesion pathway, the underlying mechanisms are currently believed to be distinct. Defects in mitotic failure and apoptosis i.e. trans DNA tethering events are believed to be the underlying cause of RBS, whereas the underlying cause of CdLS is largely modeled as occurring through defects in transcriptional processes i.e. cis DNA tethering events. Here, we review recent findings described primarily in zebrafish, paired with additional studies in other model systems, including human patient cells, which challenge the notion that cohesinopathies represent separate syndromes. We highlight numerous studies that illustrate the utility of zebrafish to provide novel insights into the phenotypes, genes affected and the possible mechanisms underlying cohesinopathies. We propose that transcriptional deregulation is the predominant mechanism through which cohesinopathies arise. Developmental Dynamics 246:881-888, 2017. V C 2017 Wiley Periodicals, Inc.

Cohesin removal reprograms gene expression upon mitotic entry

“…In addition to mitosis, gene expression shows an extensive reprogramming following cell differentiation during development. Mutations on genes encoding the cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, have been identified in the Cornelia de Lange syndrome (CdLS), a cohesinopathy causing severe developmental disorders (Banerji et al, 2017). Importantly, cells from CdLS patients exhibit no cohesion defects but significantly altered transcriptional profiles (Mannini et al, 2015), supporting a central role for cohesin and its regulation rewiring gene expression during development.…”

Condensins and cohesins – one of these things is not like the other!

“…Robert syndrome (RBS) and Cornelia de Lange syndrome (CdLS) are two cohesin-based developmental disorders that exhibit an overlapping suite of developmental defects that include cleft palate, microcephaly, profound limb reduction, syndactyly and, often, acute cognitive impairment Tonkin et al, 2004;Gillis et al, 2004;Schüle et al, 2005;Musio et al, 2006;Deardorff et al, 2007;Deardorff et al, 2012a,b;Vega et al, 2005). Given the range of tissues impacted by cohesin mutation, and the genome-wide effect that cohesins exert on gene transcription (see below), one should anticipate that the number of cohesin-related maladies or cohesinopathies (more recently termed transcriptomopathies and which include ribosomopathies) will increase significantly over time (Wendt et al, 2008;Xu et al, 2014;Yuan et al, 2015;Skibbens et al, 2013;Banerji et al, 2017a).…”

“…Zebrafish is an exceptionally useful model system to link studies of cohesin-based transcription and development (Kawauchi et al, 2016;Muto and Schilling, 2017;Banerji et al, 2017a). A key stage in development is the transition from the maternal to zygotic control of transcription (also termed zygotic genome activation; ZGA).…”

Esco2 and Cohesin Regulate CRL4 Ubiquitin Ligaseddb1Expression and Thalidomide Teratogenicity

“…Inhibition of CRL4 function is solely responsible for thalidomide teratogenicity: development proceeds normally upon thalidomide exposure in embryos expressing thalidomide-resistant CRL4 and mutation of CRL4 subunits are sufficient to produce thalidomide-induced birth defects and intellectual disabilities (4). Roberts syndrome (RBS) and Cornelia de Lange syndrome (CdLS) are severe genetic maladies in which manifestations highly resemble those observed in thalidomide babies (5,6). RBS arises through mutation of ESCO2 while CdLS arises through mutation of cohesin subunits and regulators (6).…”