Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Reis-Sobreiro, Mariana; Chen, Jie‐Fu; Novitskaya, Tatiana; You, Sungyong; Morley, Samantha; Steadman, Kenneth; Gill, Navjot Kaur; Eskaros, Adel; Rotinen, Mirja; Chu, Chia-Yi; Chung, Leland W.K.; Tanaka, Hisashi; Yang, Wei; Knudsen, Beatrice S.; Tseng, Hsian‐Rong; Rowat, Amy C.; Posadas, Edwin M.; Zijlstra, Andries; Vizio, Dolores Di

doi:10.1158/0008-5472.can-18-0608

Cited by 59 publications

(67 citation statements)

References 44 publications

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“…The bacterium Chlamydia psittaci , which causes rapid and potentially lethal pneumonia, targets emerin and emerin-associated nuclear membrane proteins (Mojica et al, 2015). In models of breast and prostate cancer, loss of emerin correlates with increased metastatic potential (Hu et al, 2011; Wozniak et al, 2013; Reis-Sobreiro et al, 2018). Mechanisms and partners for emerin in these contexts are unexplored.…”

Section: Introductionmentioning

confidence: 99%

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Dharmaraj

Guan

Liu

et al. 2019

Front. Cell Dev. Biol.

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Emerin ( EMD ) and barrier to autointegration factor 1 ( BANF1 ) each bind A-type lamins ( LMNA ) as fundamental components of nuclear lamina structure. Mutations in LMNA , EMD and BANF1 are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy ( LMNA , EMD ), lipodystrophy, insulin resistance and type 2 diabetes ( LMNA ) and progeria ( LMNA , BANF1 ). To explore human genetic variation in these genes, we analyzed EMD and BANF1 alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of EMD revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed ‘benign’ in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four ‘healthy’ traits: reduced triglycerides (-0.336; p = 0.0368), reduced waist circumference (-0.321; p = 0.0486), reduced cholesterol ( - 0.572; p = 0.000346) and reduced LDL cholesterol (-0.599; p = 0.000272). These traits are distinct from LMNA -associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (∼0.041% and ∼0.034% of non-Finnish Europeans, respectively), p.G156S (∼0.39% of Africans), p.R204G (∼0.18% of Latinx), p.R207P (∼0.08% of South Asians) and p.R221L (∼0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a ‘healthy’ lipid profile.

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Section: Introductionmentioning

confidence: 99%

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Dharmaraj

Guan

Liu

et al. 2019

Front. Cell Dev. Biol.

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“…The damaging effects of such large cellular deformations depend on levels of A-type nuclear lamins, which are critical regulators of nuclear and cellular mechanotype (Lammerding et al, 2004; Swift et al, 2013; Stephens et al, 2017). The depletion of other proteins that associate with nuclear lamins, such as the inner nuclear membrane protein emerin, similarly result in reduced mechanical stability of the nuclear envelope (Rowat et al, 2006; Reis-Sobreiro et al, 2018) as well as increased nuclear strain following mechanical stretch (Lammerding et al, 2005). The nuclear lamina also interacts with chromatin, which can further contribute to the mechanical properties of the nucleus (Pajerowski et al, 2007; Chalut et al, 2012; Schreiner et al, 2015; Stephens et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces

Gill

Kim

et al. 2019

Front. Cell Dev. Biol.

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DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1 / TOR1A gene, which encodes torsinA, a conserved luminal ATPases-associated with various cellular activities (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown. Here, we define the deformability of mouse fibroblasts lacking functional torsinA as well as human fibroblasts isolated from DYT1 dystonia patients. We find that the deletion of torsinA or the expression of torsinA containing the DYT1 dystonia-causing ΔE302/303 (ΔE) mutation results in more deformable cells. We observe a similar increased deformability of mouse fibroblasts that lack lamina-associated polypeptide 1 (LAP1), which interacts with and stimulates the ATPase activity of torsinA in vitro , as well as with the absence of the LINC complex proteins, Sad1/UNC-84 1 (SUN1) and SUN2, lamin A/C, or lamin B1. Consistent with these findings, we also determine that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 dystonia patient-derived fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results establish the foundation for future mechanistic studies of the role of cellular mechanotype and LINC-dependent nuclear-cytoskeletal coupling in regulating cell survival following exposure to mechanical stresses.

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“…4, 5, 6). Since Emerin is involved in the stability of nuclear shape [45], we consider this phenotype as the reflection of nuclear shape instability caused by the knockdown of Emerin.…”

Section: Discussionmentioning

confidence: 99%

Emerin anchors Msx1 and its protein partners at the nuclear periphery to inhibit myogenesis

Shi

Shen

et al. 2019

Cell Biosci

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Background Previous studies have shown that in myogenic precursors, the homeoprotein Msx1 and its protein partners, histone methyltransferases and repressive histone marks, tend to be enriched on target myogenic regulatory genes at the nuclear periphery. The nuclear periphery localization of Msx1 and its protein partners is required for Msx1’s function of preventing myogenic precursors from pre-maturation through repressing target myogenic regulatory genes. However, the mechanisms underlying the maintenance of Msx1 and its protein partners’ nuclear periphery localization are unknown. Results We show that an inner nuclear membrane protein, Emerin, performs as an anchor settled at the inner nuclear membrane to keep Msx1 and its protein partners Ezh2, H3K27me3 enriching at the nuclear periphery, and participates in inhibition of myogenesis mediated by Msx1. Msx1 interacts with Emerin both in C2C12 myoblasts and mouse developing limbs, which is the prerequisite for Emerin mediating the precise location of Msx1, Ezh2, and H3K27me3. The deficiency of Emerin in C2C12 myoblasts disturbs the nuclear periphery localization of Msx1, Ezh2, and H3K27me3, directly indicating Emerin functioning as an anchor. Furthermore, Emerin cooperates with Msx1 to repress target myogenic regulatory genes, and assists Msx1 with inhibition of myogenesis. Conclusions Emerin cooperates with Msx1 to inhibit myogenesis through maintaining the nuclear periphery localization of Msx1 and Msx1’s protein partners.

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Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential

Cited by 59 publications

References 44 publications

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces

Emerin anchors Msx1 and its protein partners at the nuclear periphery to inhibit myogenesis

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