SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin

Maison, Christèle; Bailly, Delphine; Roche, Danièle; de, Rocío Montes; Probst, Aline V.; Vassias, Isabelle; Dingli, Florent; Lombard, Bérengère; Loew, Damarys; Quivy, Jean‐Pierre; Almouzni, Geneviève

doi:10.1038/ng.765

Cited by 196 publications

(232 citation statements)

References 56 publications

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“…[25][26][27] HP1a is known to be involved in transcriptional silencing of gene poor pericentromeric heterochromatin by directly interacting with H3K9me3 present in these chromatin regions. [28][29][30] Although KDM2A has been studied with regards to regulation of pericentromeric heterochromatin, it is not clear from the published data whether the observed derepression of the pericentromeric repeats is caused by the absence of KDM2A-LF or by the absence of KDM2A-SF. 33 Our results show that KDM2A-SF accumulates at pericentromeric regions in an HP1a-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 52%

“…3B), a histone modification associated with transcriptionally silent heterochromatin 1,9,35 and also with HP1a (Fig. 3C), a protein associated with pericentromeric and telomeric heterochromatin, [28][29][30][31][32] 2. the KDM2A structures localize next to CENP-A (Fig. 3D), a histone variant associated with centromeric heterochromatin.…”

Section: Kdm2a-sf Forms Distinct Heterochromatic Structures In An Hp1mentioning

confidence: 99%

“…HP1a is known to directly interact with the pericentromeric H3K9me3 modification and by doing so to participate on repressing pericentromeric heterochromatin. [28][29][30][31][32] 2. KDM2A-LF and KDM2A-SF are known to directly interact with HP1a, through which they complex with H3K9me3.…”

Section: Kdm2a-sf Forms Distinct Heterochromatic Structures In An Hp1mentioning

confidence: 99%

“…[25][26][27] HP1a plays an important role in transcriptional repression of pericentromeric heterochromatin, where it directly interacts with H3K9me3 through its chromodomain. [28][29][30][31][32] Although both KDM2A-LF and KDM2A-SF are known to directly interact with HP1a, only KDM2A-LF has been studied with regards to regulation of pericentromeric heterochromatin. 33 Moreover, KDM2A-SF has been found to be overexpressed in cancer cells and to promote their proliferation most likely through its ability to induce rDNA transcription.…”

Section: Introductionmentioning

confidence: 99%

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A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

Lađinović

Novotná

Jakšová

et al. 2017

Nucleus

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Histone modifications have a profound impact on the chromatin structure and gene expression and their correct establishment and recognition is essential for correct cell functioning. Malfunction of histone modifying proteins is associated with developmental defects and diseases and detailed characterization of these proteins is therefore very important. The lysine specific demethylase KDM2A is a CpG island binding protein that has been studied predominantly for its ability to regulate CpG island-associated gene promoters by demethylating their H3K36me2. However, very little attention has been paid to the alternative KDM2A isoform that lacks the N-terminal demethylation domain, KDM2A-SF. Here we characterized KDM2A-SF more in detail and we found that, unlike the canonical full length KDM2A-LF isoform, KDM2A-SF forms distinct nuclear heterochromatic bodies in an HP1a dependent manner. Our chromatin immunoprecipitation experiments further showed that KDM2A binds to transcriptionally silent pericentromeric regions that exhibit high levels of H3K36me2. H3K36me2 is the substrate of the KDM2A demethylation activity and the high levels of this histone modification in the KDM2A-bound pericentromeric regions imply that these regions are occupied by the demethylation deficient KDM2A-SF isoform.

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Section: Discussionmentioning

confidence: 52%

Section: Kdm2a-sf Forms Distinct Heterochromatic Structures In An Hp1mentioning

confidence: 99%

Section: Kdm2a-sf Forms Distinct Heterochromatic Structures In An Hp1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

Lađinović

Novotná

Jakšová

et al. 2017

Nucleus

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“…We identified that the HP1a isoform was targeted at these domains when post-translationally modified by sumoylation, even in the absence of Suv39h-dependent H3K9me3. Importantly, we revealed a specific interaction between SUMO-HP1a and pericentric RNA transcripts 7 (Fig. 1).…”

mentioning

confidence: 98%

Suv39h1 links the SUMO pathway to constitutive heterochromatin

Maison

Quivy

Almouzni

2016

Molecular & Cellular Oncology

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The Suv39h lysine methyltransferases, known as key enzymes responsible for histone H3 lysine 9 methylation, are critical for heterochromatin protein 1 enrichment at constitutive heterochromatin. Our recent findings reveal a new role for the Suv39h1 paralog that links it to SUMO pathway function at constitutive heterochromatin. KEYWORDSHeterochromatin; HP1; nuclear organization; SUMO pathway; suv39h1Heterochromatin has long been considered an inert part of the genome, merely gathering repetitive sequences. The last 10 y of research in chromatin and epigenetics have highlighted the importance of heterochromatin features for transcriptional regulation, nuclear organization, and genomic stability in a variety of species. In particular, histone marks characteristic of constitutive heterochromatin such as histone H3 lysine 9 methylation (H3K9me3) established by distinct "writers" (i.e., the Suv39h lysine methyltransferases [KMTs] in mammals) that protein "readers" (such as heterochromatin protein 1 [HP1]) can recognize provide a paradigm for a mechanism involved in and/or associated with a plethora of genomic functions affecting cell physiology and homeostasis. Notably, these functions include global genomic stability/heritability over cellular division, with a key role at the centromere and telomeres, developmental programs and cell fate, aging and senescence, and cancer. 1-4 Whether these functions originate from the same or distinct features of constitutive heterochromatin, such as solely transcriptional repression or nuclear organization, remains to be documented. It therefore became of the utmost importance to decipher how the dynamics of heterochromatin organization are controlled and how they can be linked to changes in cellular functions during development and most critically in the context of human health. A logical approach has been to focus on the already well-identified players Suv39h, H3K9me3, and HP1 that contribute to various levels of heterochromatin organization. The Suv39h KMTs 5 ensure H3K9me3 marks at nucleosomes in heterochromatin, which in turn provide binding/anchoring sites for the HP1 proteins; the capacity of Suv39h to bind HP1 further contributes to propagation of methylation of H3K9 on neighboring nucleosomes. Once an initiating site has been established, this latter "self-sustaining" loop provides a simple maintenance system for constitutive heterochromatin at specific genomic loci. 6 Using the constitutive heterochromatin at pericentric domains (chromosomal domains flanking the microtubule attachment sites of the sister chromatids during mitosis) in mouse cells as a model, our previous studies showed that the SUMO pathway is involved in the initiation of this loop. We identified that the HP1a isoform was targeted at these domains when post-translationally modified by sumoylation, even in the absence of Suv39h-dependent H3K9me3. Importantly, we revealed a specific interaction between SUMO-HP1a and pericentric RNA transcripts 7 (Fig. 1). Interestingly, in addition to sumoylation, d...

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RNA as a Regulator of Chromatin Structure

Murakami

2014

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin

Cited by 196 publications

References 56 publications

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

Suv39h1 links the SUMO pathway to constitutive heterochromatin

RNA as a Regulator of Chromatin Structure

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