The Human Protein PRR14 Tethers Heterochromatin to the Nuclear Lamina during Interphase and Mitotic Exit

Poleshko, Andrey; Mansfield, Katelyn M.; Burlingame, Caroline; Andrake, Mark D.; Shah, Neil; Katz, Richard A.

doi:10.1016/j.celrep.2013.09.024

Cited by 103 publications

(189 citation statements)

References 46 publications

(61 reference statements)

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“…We demonstrated that PRR14 functions to tether heterochromatin to nuclear lamina, thus maintaining the peripheral nuclear heterochromatin compartment. Also, we showed that PRR14 may play a role in mitotic specification of H3K9me3-marked heterochromatin positioning at the nuclear lamina 56 , 59 …”

Section: Discussionmentioning

confidence: 73%

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Human factors and pathways essential for mediating epigenetic gene silencing

et al. 2014

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Cellular identity in both normal and disease processes is determined by programmed epigenetic activation or silencing of specific gene subsets. Here, we have used human cells harboring epigenetically silent GFP-reporter genes to perform a genome-wide siRNA knockdown screen for the identification of cellular factors that are required to maintain epigenetic gene silencing. This unbiased screen interrogated 21,121 genes, and we identified and validated a set of 128 protein factors. This set showed enrichment for functional categories, and protein-protein interactions. Among this set were known epigenetic silencing factors, factors with no previously identified role in epigenetic gene silencing, as well as unstudied factors. The set included non-nuclear factors, for example, components of the integrin-adhesome. A key finding was that the E1 and E2 enzymes of the small ubiquitin-like modifier (SUMO) pathway (SAE1, SAE2/UBA2, UBC9/UBE2I) are essential for maintenance of epigenetic silencing. This work provides the first genome-wide functional view of human factors that mediate epigenetic gene silencing. The screen output identifies novel epigenetic factors, networks, and mechanisms, and provides a set of candidate targets for epigenetic therapy and cellular reprogramming.

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Section: Discussionmentioning

confidence: 73%

“…We have investigated in detail the function of the factor, PRR14 56 . It was shown recently that the nuclear lamina plays an important role in maintaining an epigenetically silent heterochromatin compartment at the nuclear periphery 57 , 58 .…”

Section: Discussionmentioning

confidence: 99%

Human factors and pathways essential for mediating epigenetic gene silencing

et al. 2014

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“…Studies have focused on identifying proteins that tether chromatin to the lamina (Gonzalez-Sandoval et al, 2015; Poleshko et al, 2013; Solovei et al, 2013) as well as defining the critical epigenetic histone modifications and enzymes involved in regulation of nuclear architecture (Gonzalez-Sandoval et al, 2015; Guelen et al, 2008; Harr et al, 2015; Kind et al, 2015; Kind et al, 2013; Therizols et al, 2014; Towbin et al, 2012). One such factor is Hdac3, a histone deacetylase (HDAC) that interacts at the inner nuclear membrane with multiple proteins, including Lamina-associated polypeptide 2 (Lap2β; Somech et al, 2005; Zullo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction

Poleshko

Shah

Gupta

et al. 2017

Cell

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Summary Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin and, independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.

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“…In most cells, at least one class of heterochromatin is positioned at the nuclear lamina, resulting in gene repression (Andrulis et al, 1998;Finlan et al, 2008;Guelen et al, 2008;Kumaran and Spector, 2008;Peric-Hupkes et al, 2010;Reddy et al, 2008;Solovei et al, 2013;Towbin et al, 2012). Previous studies also propose that heterochromatin relocation to the nuclear lamina might occur via active tethering mediated by discrete molecular complexes (Chubb et al, 2002;Poleshko et al, 2013). These perinuclear heterochromatin hotspots are enriched with histone 3 lysine 9 dimethylation (H3K9me2) and trimethylation (H3K9me3) modifications, which are usually associated with a number of heterochromatin binding proteins such as KRAB-associated protein 1 (KAP1/TIF1b/TRIM28), a binding partner of histonelysine N-methyltransferase SETDB1 (Grewal and Jia, 2007;Nielsen et al, 1999;Ryan et al, 1999;Zeng et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

LMTK3 Represses Tumor Suppressor-like Genes through Chromatin Remodeling in Breast Cancer

Zhang

Nguyen

et al. 2015

Cell Reports

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LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is localized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling.

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The Human Protein PRR14 Tethers Heterochromatin to the Nuclear Lamina during Interphase and Mitotic Exit

Cited by 103 publications

References 46 publications

Human factors and pathways essential for mediating epigenetic gene silencing

Human factors and pathways essential for mediating epigenetic gene silencing

Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction

LMTK3 Represses Tumor Suppressor-like Genes through Chromatin Remodeling in Breast Cancer

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