Coaching from the sidelines: the nuclear periphery in genome regulation

Buchwalter, Abigail; Kaneshiro, Jeanae M.; Hetzer, Martin W.

doi:10.1038/s41576-018-0063-5

Cited by 166 publications

(149 citation statements)

References 167 publications

(252 reference statements)

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“…In order for a dividing cell of a given lineage to maintain its identity, it must pass along to its 2 progeny not only a complete copy of its genome, but also the memory of its specific cellular 3 identity (Buchwalter et al, 2019, Towbin et al, 2013, Amendola and van Steensel, 2014. It is transcriptional repression.…”

Section: Introductionmentioning

confidence: 99%

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

Poleshko

Smith

Nguyen

et al. 2019

Preprint

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Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression and identity.Here we show that histone 3 lysine 9 dimethylation (H3K9me2) is an evolutionarily conserved, specific mark of nuclear peripheral heterochromatin and that it is retained through mitosis. During mitosis, phosphorylation of histone 3 serine 10 temporarily shields the H3K9me2 mark allowing for dissociation of chromatin from the nuclear lamina. Using high-resolution 3D immuno-oligoFISH, we demonstrate that H3K9me2-enriched genomic regions, which are positioned at the nuclear lamina in interphase cells prior to mitosis, reassociate with the forming nuclear lamina before mitotic exit. The H3K9me2 modification of peripheral heterochromatin ensures that positional information is safeguarded through cell division such that individual LADs are re-established at the nuclear periphery in daughter nuclei. Thus, H3K9me2 acts as a 3D architectural mitotic guidepost. Our data establish a mechanism for epigenetic memory and inheritance of spatial organization of the genome.maintenance of cellular identity (Zullo et al., 2012, Poleshko et al., 2017 2010). LADs are defined by their interaction with the nuclear lamina which is disassembled during 33 cell division, posing a conundrum as to how cell-type specific LADs are remembered through 34 mitosis. 35The molecular mechanisms by which LADs are established and maintained at the nuclear 36 periphery remain poorly understood. For example, there does not appear to be a clear targeting 37 sequence that localizes areas of the genome to the nuclear periphery (Zullo et al., 2012, Meuleman 38 et al., 2013. However, histone post-translational modifications have been implicated in LAD 39 regulation. Proline Rich Protein 14 (PRR14) has been shown to recognize H3K9me3, found on 40 both peripheral and nucleoplasmic heterochromatin, through an interaction with HP1 (Poleshko et 41 al., 2013). In addition, work from our group and others has demonstrated a specific enrichment for 42 H3K9me2 at the nuclear periphery, raising the possibility of a regulatory role in LAD positioning 43 (Poleshko et al., 2017, Kind et al., 2013). CEC-4, a C. elegans chromodomain-containing protein, 44 localizes to the nuclear periphery and has been shown to be a reader of H3K9 methylated chromatin 45 (Gonzalez-Sandoval et al., 2015). Depletion studies using RNAi and loss-of-function mutants 46 demonstrated that CEC-4 is required for peripheral heterochromatin anchoring but not 47 62Pioneering studies in the 1980s revealed the necessity for DNA in the process of nuclear lamina 63 reassembly after mitosis, and the activity of kinases and phosphatases were implicated in 6...

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Section: Introductionmentioning

confidence: 99%

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

Poleshko

Smith

Nguyen

et al. 2019

Preprint

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“…There is considerable interest in understanding how the heterochromatin compartment is organized at the nuclear envelope, and how lineage-inappropriate genes are silenced through such positioning (Amendola and van Steensel, 2014;Buchwalter et al, 2019;Gordon et al, 2015;Gruenbaum and Foisner, 2015;Harr et al, 2016;Lemaitre and Bickmore, 2015;Meister and Taddei, 2013;Padeken and Heun, 2014;Poleshko et al, 2017;Politz et al, 2013;Shevelyov and Nurminsky, 2012;Shevelyov and Ulianov, 2019;Ungricht and Kutay, 2015;van Steensel and Belmont, 2017;Wong and Reddy, 2015;Yanez-Cuna and van Steensel, 2017;Zullo et al, 2012). Emerging research findings have pointed to an evolutionarily conserved mechanism whereby a class of three "tethering proteins" function to organize H3K9me-modified heterochromatin at the nuclear periphery (Gonzalez-Sandoval et al, 2015;Harr et al, 2016;Kind et al, 2013;Poleshko et al, 2013;Towbin et al, 2013;van Steensel and Belmont, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The eukaryotic DNA genome is organized into chromatin and is enclosed by the nuclear envelope that forms the border of the nuclear organelle. The nuclear envelope is a double membrane (Buchwalter et al, 2019;Hetzer, 2010;Ungricht and Kutay, 2015) that in multicellular organisms, includes the nuclear lamina protein framework that lies underneath the inner nuclear membrane (Dittmer and Misteli, 2011;Gruenbaum and Foisner, 2015). The nuclear lamina is composed of the intermediate filament proteins Lamin A/C, Lamin B1 and Lamin B2.…”

Section: Introductionmentioning

confidence: 99%

“…The nuclear lamina is composed of the intermediate filament proteins Lamin A/C, Lamin B1 and Lamin B2. In addition to acting as a nuclear framework, the nuclear lamina serves as a docking site for heterochromatin, which forms a characteristic silent "peripheral heterochromatin compartment" decorated with the repressive heterochromatic histone tail modifications, histone 3 lysine 9 di-and tri-methyl (H3K9me2 and H3K9me3) (Buchwalter et al, 2019;Gordon et al, 2015;Gruenbaum and Foisner, 2015;Lemaitre and Bickmore, 2015;Meister and Taddei, 2013;Padeken and Heun, 2014;Politz et al, 2013;Shevelyov and Nurminsky, 2012;Shevelyov and Ulianov, 2019;van Steensel and Belmont, 2017;Wong and Reddy, 2015). This heterochromatin compartment positioned at the nuclear lamina is the focus of much interest, as it provides a critical function in housing lineage-inappropriate repressed genes and gene-poor DNA (Becker et al, 2016;Peric-Hupkes et al, 2010;Reddy et al, 2008;Stancheva and Schirmer, 2014;Zhou et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting

Dunlevy

Medvedeva

Wilson

et al. 2019

Preprint

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AbstractA large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via “tethering proteins” that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We identified previously a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify a centrally located, evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We also show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation of the LBD. We also show that the evolutionary conserved PRR14 C-terminal Tantalus domain encodes a PP2A phosphatase recognition site that regulates PRR14 nuclear lamina association. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two modular domains. Furthermore, the identification of a modular LBD may provide an engineering strategy for delivery of cargo to the nuclear lamina.

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“…Recent studies have utilized chromosome conformation capture techniques like 3-C and Hi-C to infer 3D genome organization by analyzing interaction frequencies between different regions of the genome [96]. Such studies have revealed a genome organization in which chromosomes occupy distinct territories in nuclear space and then fold into gene-rich and transcriptionally active or gene-poor & transcriptionally repressed compartments (referred to as A and B compartment respectively) [97]. These compartments are further divided into topologically associated domains (TADs) that are enriched for local genomic interactions and conserved across cell types and species.…”

Section: Neurogenesis As a Paradigm To Study The Role Of Actin In Genmentioning

confidence: 99%

Emerging roles of cytoskeletal proteins in regulating gene expression and genome organization during differentiation

Xie

Mahmood

Gjorgjieva

et al. 2020

Nucleus

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In the eukaryotic cell nucleus, cytoskeletal proteins are emerging as essential players in nuclear function. In particular, actin regulates chromatin as part of ATP-dependent chromatin remodeling complexes, it modulates transcription and it is incorporated into nascent ribonucleoprotein complexes, accompanying them from the site of transcription to polyribosomes. The nuclear actin pool is undistinguishable from the cytoplasmic one in terms of its ability to undergo polymerization and it has also been implicated in the dynamics of chromatin, regulating heterochromatin segregation at the nuclear lamina and maintaining heterochromatin levels in the nuclear interiors. One of the next frontiers is, therefore, to determine a possible involvement of nuclear actin in the functional architecture of the cell nucleus by regulating the hierarchical organization of chromatin and, thus, genome organization. Here, we discuss the repertoire of these potential actin functions and how they are likely to play a role in the context of cellular differentiation. ARTICLE HISTORY

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Coaching from the sidelines: the nuclear periphery in genome regulation

Cited by 166 publications

References 167 publications

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting

Emerging roles of cytoskeletal proteins in regulating gene expression and genome organization during differentiation

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