A transcription factor–based mechanism for mouse heterochromatin formation

Bulut-Karslıoğlu, Aydan; Perrera, Valentina; Scaranaro, Manuela; Rosa-Velázquez, Inti A. De La; Nobelen, Suzanne van de; Shukeir, Nicholas; Popow, Johannes; Gerle, Borbala; Opravil, Susanne; Pagani, Michaela; Meidhof, Simone; Brabletz, Thomas; Manke, Thomas; Lachner, Monika; Jenuwein, Thomas

doi:10.1038/nsmb.2382

Cited by 160 publications

(150 citation statements)

References 52 publications

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“…These special properties of heterochromatin are established in a step-wise manner. First, specific proteins need to recognize heterochromatic sequences (Bulut-Karslioglu et al 2012). Second, heterochromatin becomes marked with distinct histone modifications that recruit additional binding proteins to ultimately mediate the special properties of this chromatin state.…”

Section: Discussionmentioning

confidence: 99%

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin

et al. 2013

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Cohesin plays an important role in chromatid cohesion and has additional functions in higher-order chromatin organization and in transcriptional regulation. The binding of cohesin to euchromatic regions is largely mediated by CTCF or the mediator complex. However, it is currently unknown how cohesin is recruited to pericentric heterochromatin in mammalian cells. Here we define the histone methyltransferase Suv4-20h2 as a major structural constituent of heterochromatin that mediates chromatin compaction and cohesin recruitment. Suv4-20h2 stably associates with pericentric heterochromatin through synergistic interactions with multiple heterochromatin protein 1 (HP1) molecules, resulting in compaction of heterochromatic regions. Suv4-20h mutant cells display an overall reduced chromatin compaction and an altered chromocenter organization in interphase referred to as ''chromocenter scattering.'' We found that Suv4-20h-deficient cells display chromosome segregation defects during mitosis that coincide with reduced sister chromatid cohesion. Notably, cohesin subunits interact with Suv4-20h2 both in vitro and in vivo. This interaction is necessary for cohesin binding to heterochromatin, as Suv4-20h mutant cells display substantially reduced cohesin levels at pericentric heterochromatin. This defect is most prominent in G0-phase cells, where cohesin is virtually lost from heterochromatin, suggesting that Suv4-20h2 is involved in the initial loading or maintenance of cohesion subunits. In summary, our data provide the first compelling evidence that Suv4-20h2 plays essential roles in regulating nuclear architecture and ensuring proper chromosome segregation.

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Section: Discussionmentioning

confidence: 99%

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin

et al. 2013

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“…Inasmuch as DNA methylation in the linker region is recognized by methyl-binding proteins, it could contribute to enriching a dinucleosome particle during the MNase digestion step. Such a complex consisting of a 5mC-recognizing protein binding to the linker DNA between two nucleosomes might be important for the formation of heterochromatic regions (Bulut-Karslioglu et al 2012) and intron/exon recognition during the cotranscriptional splicing (Gelfman et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development

et al. 2014

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During differentiation of embryonic stem cells, chromatin reorganizes to establish cell type-specific expression programs. Here, we have dissected the linkages between DNA methylation (5mC), hydroxymethylation (5hmC), nucleosome repositioning, and binding of the transcription factor CTCF during this process. By integrating MNase-seq and ChIP-seq experiments in mouse embryonic stem cells (ESC) and their differentiated counterparts with biophysical modeling, we found that the interplay between these factors depends on their genomic context. The mostly unmethylated CpG islands have reduced nucleosome occupancy and are enriched in cell type-independent binding sites for CTCF. The few remaining methylated CpG dinucleotides are preferentially associated with nucleosomes. In contrast, outside of CpG islands most CpGs are methylated, and the average methylation density oscillates so that it is highest in the linker region between nucleosomes. Outside CpG islands, binding of TET1, an enzyme that converts 5mC to 5hmC, is associated with labile, MNase-sensitive nucleosomes. Such nucleosomes are poised for eviction in ESCs and become stably bound in differentiated cells where the TET1 and 5hmC levels go down. This process regulates a class of CTCF binding sites outside CpG islands that are occupied by CTCF in ESCs but lose the protein during differentiation. We rationalize this cell type-dependent targeting of CTCF with a quantitative biophysical model of competitive binding with the histone octamer, depending on the TET1, 5hmC, and 5mC state.

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“…NANOG associates with major satellite repeats in ESCs. (A) His-tagged recombinant wild-type and N51A mutant NANOG homeodomains were used for electrophoretic mobility shift assays with a full-length major satellite probe (234 bp) (Bulut-Karslioglu et al 2012) and a Tcf3 probe (14 bp) (Jauch et al 2008). (B) ChIP-qPCR analysis of NANOG at major satellite, LINE, SINE, and IAP DNA in wild-type and Nanog -/-ESCs.…”

Section: The Nanog Transactivation Domain Is Critical For Heterochrommentioning

confidence: 99%

“…The chromatin environment of constitutive pericentromeric heterochromatin (PCH) has been well characterized in somatic cells and shown to contain condensed chromatin fibers and high levels of histone H3 Lys9 trimethylation (H3K9me3) that is mediated by Suv39h1/2 methyltransferases (Peters et al 2001;Lehnertz et al 2003). The major satellite DNA repeats within PCH are typically transcriptionally repressed yet remain accessible to DNA-binding factors and are responsive to transcriptional regulation (Bulut-Karslioglu et al 2012). Deletion of epigenetic regulators (including Suv39h1/2 and Dicer) in mouse somatic cells perturbs PCH identity, causes the transcriptional upregulation of major satellite sequences, and is associated with severe chromosome missegregation phenotypes (Peters et al 2001;Kanellopoulou et al 2005).…”

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confidence: 99%

The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells

et al. 2016

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An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells.

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A transcription factor–based mechanism for mouse heterochromatin formation

Cited by 160 publications

References 52 publications

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin

Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development

The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells

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