scholarly journals The effect of Nipped-B-Like (Nipbl) haploinsufficiency on genome-wide cohesin binding and target gene expression: modeling Cornelia de Lange Syndrome

2017 ◽  
Author(s):  
Daniel A. Newkirk ◽  
Yen-Yun Chen ◽  
Richard Chien ◽  
Weihua Zeng ◽  
Jacob Biesinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sister Chromatid ◽  
Target Genes ◽  
Sister Chromatid Cohesion ◽  
Ctcf Binding ◽  
Cornelia De Lange Syndrome ◽  
Specific Expression ◽  
Genome Wide ◽  
Chromatid Cohesion ◽  
Cornelia De Lange

ABSTRACTCornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

scholarly journals NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome

2004 ◽  
Vol 36 (6) ◽  
pp. 636-641 ◽  
Author(s):  
Emma T Tonkin ◽  
Tzu-Jou Wang ◽  
Steven Lisgo ◽  
Michael J Bamshad ◽  
Tom Strachan
Keyword(s):  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Cornelia De Lange Syndrome ◽  
Chromatid Cohesion ◽  
Cornelia De Lange

scholarly journals Rec8p, a Meiotic Recombination and Sister Chromatid Cohesion Phosphoprotein of the Rad21p Family Conserved from Fission Yeast to Humans

1999 ◽  
Vol 19 (5) ◽  
pp. 3515-3528 ◽  
Author(s):  
Sandro Parisi ◽  
Michael J. McKay ◽  
Monika Molnar ◽  
M. Anne Thompson ◽  
Peter J. van der Spek ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Sister Chromatid ◽  
Germ Line ◽  
Sequence Similarity ◽  
Sister Chromatid Cohesion ◽  
Specific Expression ◽  
Chromatid Cohesion ◽  
Prophase Nucleus ◽  
Chromosome Iii ◽  
Meiosis I

ABSTRACT Our work and that of others defined mitosis-specific (Rad21 subfamily) and meiosis-specific (Rec8 subfamily) proteins involved in sister chromatid cohesion in several eukaryotes, including humans. Mutation of the fission yeast Schizosaccharomyces pombe rec8 gene was previously shown to confer a number of meiotic phenotypes, including strong reduction of recombination frequencies in the central region of chromosome III, absence of linear element polymerization, reduced pairing of homologous chromosomes, reduced sister chromatid cohesion, aberrant chromosome segregation, defects in spore formation, and reduced spore viability. Here we extend the description of recombination reduction to the central regions of chromosomes I and II. We show at the protein level that expression ofrec8 is meiosis specific and that Rec8p localizes to approximately 100 foci per prophase nucleus. Rec8p was present in an unphosphorylated form early in meiotic prophase but was phosphorylated prior to meiosis I, as demonstrated by analysis of the mei4mutant blocked before meiosis I. Evidence for the persistence of Rec8p beyond meiosis I was obtained by analysis of the mutantmes1 blocked before meiosis II. A human gene, which we designate hrec8, showed significant primary sequence similarity to rec8 and was mapped to chromosome 14. High mRNA expression of mouse and human rec8 genes was found only in germ line cells, specifically in testes and, interestingly, in spermatids. hrec8 was also expressed at a low level in the thymus. Sequence similarity and testis-specific expression indicate evolutionarily conserved functions of Rec8p in meiosis. Possible roles of Rec8p in the integration of different meiotic events are discussed.

scholarly journals Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells

2015 ◽  
Vol 112 (36) ◽  
pp. 11270-11275 ◽  
Author(s):  
Sadia Rahman ◽  
Mathew J. K. Jones ◽  
Prasad V. Jallepalli
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Sister Chromatid ◽  
Target Genes ◽  
Somatic Cells ◽  
S Phase ◽  
Cohesin Complex ◽  
Genome Wide ◽  
Chromatid Cohesion ◽  
Eukaryotic Genomes

The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells.

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