The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications

Jahnke, Philipp; Xu, Weizhen; Wülling, Manuela; Albrecht, Melanie; Gabriel, Heinz; Gillessen‐Kaesbach, Gabriele; Kaiser, Frank J.

doi:10.1093/nar/gkn688

Cited by 56 publications

(48 citation statements)

References 36 publications

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“…In addition, cohesin/Nipbl may play an active role in gene silencing. A recent study reported the interaction of Nipbl with histone deacetylases, indicative of its role in promoting deacetylation and transcriptional silencing (44). We previously found the binding of cohesin to heterochromatic repeat regions in human cells, which is Nipbldependent but CTCF-independent, also suggesting its link to repressive chromatin organization and gene silencing (15).…”

Section: Discussionmentioning

confidence: 83%

Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression

Chien¹,

Zeng²,

Kawauchi³

et al. 2011

Journal of Biological Chemistry

106

118

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The ␤-globin locus undergoes dynamic chromatin interaction changes in differentiating erythroid cells that are thought to be important for proper globin gene expression. However, the underlying mechanisms are unclear. The CCCTC-binding factor, CTCF, binds to the insulator elements at the 5 and 3 boundaries of the locus, but these sites were shown to be dispensable for globin gene activation. We found that, upon induction of differentiation, cohesin and the cohesin loading factor Nipped-B-like (Nipbl) bind to the locus control region (LCR) at the CTCF insulator and distal enhancer regions as well as at the specific target globin gene that undergoes activation upon differentiation. Nipbl-dependent cohesin binding is critical for long-range chromatin interactions, both between the CTCF insulator elements and between the LCR distal enhancer and the target gene. We show that the latter interaction is important for globin gene expression in vivo and in vitro. Furthermore, the results indicate that such cohesin-mediated chromatin interactions associated with gene regulation are sensitive to the partial reduction of Nipbl caused by heterozygous mutation. This provides the first direct evidence that Nipbl haploinsufficiency affects cohesin-mediated chromatin interactions and gene expression. Our results reveal that dynamic Nipbl/cohesin binding is critical for developmental chromatin organization and the gene activation function of the LCR in mammalian cells.

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Section: Discussionmentioning

confidence: 83%

Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression

Chien¹,

Zeng²,

Kawauchi³

et al. 2011

Journal of Biological Chemistry

106

118

View full text Add to dashboard Cite

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“…Key roles for cohesin have been shown in a number of cellular processes including DNA repair, 21,22 chromatin modification, 23 DNA condensation 24 and transcriptional regulation in Drosophila, [25][26][27][28] [36][37][38] have demonstrated that the function of Scc2/NIPBL in sister chromatid cohesion is spatially and temporally associated with that of Scc4/MAU2. The C. elegans homolog mau-2 was originally identified for its role in axon guidance 39 and has subsequently been show to have a role in mitotic chromosome segregation.…”

Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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“…Fission yeast Swi6 is a histone-binding factor required for cohesin association with heterochromatin (Pidoux and Allshire, 2005;Bernard et al, 2001;Nonaka et al, 2002). Intriguingly, the cohesin deposition factor NIPBL (Scc2 in yeast) binds to histone deacetylases in vertebrate cells, potentially linking cohesin deposition to histone modification (Jahnke et al, 2008). The histone deacetylase Sir2 is required for the binding of cohesin to repressed heterochromatin (repressed mating-type loci and rDNA in yeast), although the underlying mechanism appears to involve physical recruitment rather than enzymatic function (Chang et al, 2005;Kobayashi et al, 2004;Wu et al, 2011).…”

Section: A Code For All Processesmentioning

confidence: 99%

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

Rudra

Skibbens

2013

Journal of Cell Science

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SummarySister chromatid tethering is maintained by cohesin complexes that minimally contain Smc1, Smc3, Mcd1 and Scc3. During S-phase, chromatin-associated cohesins are modified by the Eco1/Ctf7 family of acetyltransferases. Eco1 proteins function during S phase in the context of replicated sister chromatids to convert chromatin-bound cohesins to a tethering-competent state, but also during G2 and M phases in response to double-stranded breaks to promote error-free DNA repair. Cohesins regulate transcription and are essential for ribosome biogenesis and complete chromosome condensation. Little is known, however, regarding the mechanisms through which cohesin functions are directed. Recent findings reveal that Eco1-mediated acetylation of different lysine residues in Smc3 during S phase promote either cohesion or condensation. Phosphorylation and SUMOylation additionally impact cohesin functions. Here, we posit the existence of a cohesin code, analogous to the histone code introduced over a decade ago, and speculate that there is a symphony of posttranslational modifications that direct cohesins to function across a myriad of cellular processes. We also discuss evidence that outdate the notion that cohesion defects are singularly responsible for cohesion-mutant-cell inviability. We conclude by proposing that cohesion establishment is linked to chromatin formation.

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The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications

Cited by 56 publications

References 36 publications

Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression

Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

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