A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression

Abstract

The cohesin complex spatially organizes interphase chromatin by bringing distal genomic loci into close physical proximity, looping out the intervening DNA. Mutation of cohesin complex subunits is observed in cancer and developmental disorders, but the mechanisms through which these mutations may contribute to disease remain poorly understood. Here, we investigate a recurrent missense mutation to the hinge domain of the cohesin subunit SMC1A, observed in acute myeloid leukemia. Engineering this mutation into murine embryonic stem cells caused widespread changes in gene expression, including dysregulation of the pluripotency gene expression program. This mutation reduced cohesin levels at promoters and enhancers, decreased DNA loops and interactions across short genomic distances, and weakened insulation at CTCF-mediated DNA loops. These findings provide insight into how altered cohesin function contributes to disease and identify a requirement for the cohesin hinge domain in three-dimensional chromatin structure.

How can same-gene mutations promote both cancer and developmental disorders?

“…Leucine-zipper transcription regulator 1 (LZTR1), a highly mutated tumor suppressor gene involved in several cancer types and developmental disorders, is one example ( 97 , 98 ). Cohesin, a chromosome-associated multi-subunit protein complex ( 99 ), is another, possibly due to chromatin association. Chromatin regulators appear to be among the most frequently mutated genes in individuals with autism, and single-cell transcriptomics supports a role of CHD8, a DNA helicase that acts as a chromatin remodeling factor and regulates transcription in autism ( 100 , 101 ).…”

“…a chromosome-associated multi-subunit protein complex (99), is another, possibly due to chromatin association. Chromatin regulators appear to be among the most frequently mutated genes in individuals with autism, and single-cell transcriptomics supports a role of CHD8, a DNA helicase that acts as a chromatin remodeling factor and regulates transcription in autism (100,101).…”

The multifaceted roles of cohesin in cancer

“…Mutations interfere with cohesin localization to promoters and enhancers resulting in transcription dysregulation. In addition, mutated cohesin impairs the ability to organize chromatin into loops and the communication between regulatory elements such as enhancers and promoters [ 144 , 145 ].…”

Topologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease

“…It is worth to remark that mutations in the coding sequence or miss-expression of architectural proteins, i.e., cohesin and CTCF, can lead to a wide set of human pathological phenotypes ( Singh and Gerton, 2015 ). For example, somatic mutations in cohesin have been associated with different forms of cancer ( Mullenders et al, 2015 ; Fisher et al, 2017 ; Carico et al, 2021 ), which is also related to the important role of cohesin in the separation of sister chromatids during cell division ( Nasmyth and Haering, 2009 ). In addition, CTCF has been proposed as a tumor suppressor gene, since mutations in its coding sequence have also been detected in different types of cancer ( Filippova et al, 2002 ).…”