Abstract

The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.

Highlights

  • Genomes need to be stably inherited over numerous cell generations

  • The cohesin complex is crucial for chromosome segregation during cell divisions but was recently implicated in transcriptional regulation and chromatin architecture

  • Cohesin’s binding to chromatin depends on NIPBL, a factor that was found to be mutated in 50% of the cases of the human developmental disorder Cornelia de Lange Syndrome (CdLS)

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Summary

Introduction

Genomes need to be stably inherited over numerous cell generations. For each cell division the genetic information has to be replicated, the copies identified and distributed between daughter cells. Cohesin is important for DNA damage repair (for review see [2]), for chromatin insulation in cooperation with the chromatin insulator protein CCCTC-binding factor (CTCF) [3,4,5], for chromosomal long-range interactions [6,7,8], and for development [9,10,11,12]. The latter functions implicate cohesin in regulating gene expression; a large number of genes are misregulated after cohesin depletion [3,13]

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