Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome.

Steve Bilodeau,Fabien C Lamaze,Ian D Krantz,Linda Mannini,Antonio Musio,Ilaria M Rizzo,Francesco Cucco,Valentina Quarantotti,Clelia Amato

doi:10.1038/srep16803

Abstract

In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.

Highlights

Cohesin, a tripartite complex, mediates cohesion of sister chromatids after DNA replication in order to ensure faithful chromosome segregation
Cohesin binds the chromatin near the transcription start site of a number of genes and many reports show that cohesin co-localizes with CTCF in mammalian cells, where they play multiple roles in chromatin organization[14,15,16,17,18,19,20,21]
Cornelia de Lange syndrome (CdLS) is caused by mutations in five genes, NIPBL, SMC1A, SMC3, RAD21 and HDAC8, which take into account about 80% of CdLS cases

Summary

Introduction

A tripartite complex, mediates cohesion of sister chromatids after DNA replication in order to ensure faithful chromosome segregation. Cohesin is involved in additional biological processes such as DNA damage response, genome surveillance and stability and regulation of gene expression[1,10,11,12]. CdLS cell lines exhibit altered transcriptional profiles, suggesting that CdLS is the result of gene expression dysregulation by a cohesin-dependent mechanism[34]. We identified differentially expressed genes between normal and SMC1A-mutated human lymphoblastoid cell lines by using microarrays. Our results indicate that cohesin-binding genes are preferentially dysregulated in CdLS and indicate that SMC1A mutations affect Pol II and phosphorylated Pol II activity leading to gene expression dysregulation typical of CdLS

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