An EDMD Mutation in C. elegans Lamin Blocks Muscle-Specific Gene Relocation and Compromises Muscle Integrity

Mattout, Anna; Pike, Brietta L.; Towbin, Benjamin D.; Bank, Erin M.; Gonzalez‐Sandoval, Adriana; Stadler, Michael; Meister, Peter; Gruenbaum, Yosef; Gasser, Susan M.

doi:10.1016/j.cub.2011.08.030

Cited by 125 publications

(148 citation statements)

References 52 publications

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“…On the other hand, it has been demonstrated that lamin A/C establishes direct interactions with histone deacetylases including SIRT1 (Cenni et al, 2014; Liu et al, 2012), SIRT6 (Ghosh, Liu, Wang, Hao, & Zhou, 2015), and HDAC1 (Kubben et al, 2016), while lamin partners at the nuclear envelope such as emerin, BAF, and LAP2beta interact with HDAC3 (Demmerle, Koch, & Holaska, 2013) or HDAC2 (Tsai et al, 2015). Moreover, lamin A/C has been demonstrated to bind gene promoters or neighboring domains and this binding has been linked to distinct transcriptional outcomes (Lee, Welton, Smith, & Kennedy, 2009; Lund & Collas, 2013; Mattout et al, 2011). Finally, a clear link has been established between stress‐induced chromatin remodeling, including acetylation or methylation of HDAC2 substrates H3 histone lysine 9 (H3K9) and H4 histone lysine 16 (H4K16), and lamin A/C posttranslational modifications (Ghosh et al, 2015; Lattanzi et al, 2007, 2014 ; Liu et al, 2013; Mattioli et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm . Other lmn-1 mutations associated with Emery-Dreifuss muscular dystrophy affect muscle-specific gene expression (Mattout et al 2011) and have tissue-specific effects on mechanical properties of the nucleus (Zuela et al 2016). The Zuela et al study is especially significant because it examined the mechanical properties of the nucleus in an intact organism, unlike previous studies that were done using tissue culture.…”

Section: Components Of the Nementioning

confidence: 58%

“…In an effort to understand the underlying mechanism of various laminopathies, a number of disease-related lamin mutations have been introduced into C. elegans. Many of these mutations disrupted C. elegans LMN-1 oligomerization in vitro and lamin function in vivo (Wiesel et al 2008;Bank et al 2011Bank et al , 2012Mattout et al 2011;Zuela et al 2016). For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm .…”

Section: Components Of the Nementioning

confidence: 99%

“…On the NE side, the C. elegans nuclear lamina proteins LMN-1, EMR-1, and LEM-2 are all involved in tethering chromatin to the nuclear periphery (Mattout et al 2011), as is the case in mammalian cells. Downregulation of LMN-1 or codownregulation of EMR-1 and LEM-2 leads a detachment of large heterochromatin arrays from the nuclear periphery (Mattout et al 2011).…”

Section: Features Of C Elegans Chromosome Organizationmentioning

confidence: 99%

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Cell Biology of the Caenorhabditis elegans Nucleus

Cohen-Fix

Askjaer

2017

Genetics

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Studies on the Caenorhabditis elegans nucleus have provided fascinating insight to the organization and activities of eukaryotic cells. Being the organelle that holds the genetic blueprint of the cell, the nucleus is critical for basically every aspect of cell biology. The stereotypical development of C. elegans from a one cell-stage embryo to a fertile hermaphrodite with 959 somatic nuclei has allowed the identification of mutants with specific alterations in gene expression programs, nuclear morphology, or nuclear positioning. Moreover, the early C. elegans embryo is an excellent model to dissect the mitotic processes of nuclear disassembly and reformation with high spatiotemporal resolution. We review here several features of the C. elegans nucleus, including its composition, structure, and dynamics. We also discuss the spatial organization of chromatin and regulation of gene expression and how this depends on tight control of nucleocytoplasmic transport. Finally, the extensive connections of the nucleus with the cytoskeleton and their implications during development are described. Most processes of the C. elegans nucleus are evolutionarily conserved, highlighting the relevance of this powerful and versatile model organism to human biology.KEYWORDS Caenorhabditis elegans; chromatin; gene expression; lamin; LEM-domain proteins; LINC; P granule; nuclear pore complex; nuclear envelope; nucleocytoplasmic transport; nucleolus; WormBook TABLE OF CONTENTSAbstract 25 C. elegans as a model system to study cell biology of the nucleus 26 Structural components of the nucleus 27

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“…LADs have initially been discovered by DamID (DNA adenine methyltransferase [Dam] identification, a proximity assay). 2 Features of LADs include residence in overall transcriptionally silent heterochromatin 2,9 consistent with enrichment of this compartment at the nuclear periphery, 5,10,11 and a gene-poor content. 2 Large chromatin domains with similar properties have also been identified by chromatin immunoprecipitation (ChIP) of lamin A/C (referred to here as LMNA) or lamin B1 (LMNB1) coupled to array hybridization 12 or highthroughput sequencing (ChIP-seq).…”

Section: Introductionmentioning

confidence: 99%

Distinct features of lamin A-interacting chromatin domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin

Lund

Duband-Goulet

Oldenburg

et al. 2015

Nucleus

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The nuclear lamina has been shown to interact with the genome through lamina-associated domains (LADs). LADs have been identified by DamID, a proximity labeling assay, and more recently by chromatin immunoprecipitationsequencing (ChIP-seq) of A-and B-type lamins. LADs form megabase-size domains at the nuclear periphery, they are gene-poor and mostly heterochromatic. Here, we show that the mode of chromatin fragmentation for ChIP, namely bath sonication or digestion with micrococcal nuclease (MNase), leads to the discovery of common but also distinct sets of lamin-interacting domains, or LiDs. Using ChIP-seq, we show the existence of lamin A/C (LMNA) LiDs with distinct gene contents, histone composition enrichment and relationships to lamin B1-interacting domains. The extent of genome coverage of lamin A/C (LMNA) LiDs in sonicated or MNase-digested chromatin is similar (»730 megabases); however over half of these domains are uniquely detected in sonicated or MNase-digested chromatin. Sonicationspecific LMNA LiDs are gene-poor and devoid of a broad panel of histone modifications, while MNase-specific LMNA LiDs are of higher gene density and are enriched in H3K9me3, H3K27me3 and in histone variant H2A.Z. LMNB1 LiDs are gene-poor and show no or little enrichment in these marks. Comparison of published LMNB1 DamID LADs with LMNB1 and LMNA LiDs identified here by ChIP-seq further shows that LMNA can associate with 'open' chromatin domains displaying euchromatin characteristics, and which are not associated with LMNB1. The differential genomic and epigenetic properties of lamin-interacting domains reflect the existence of distinct LiD populations identifiable in different chromatin contexts, including nuclease-accessible regions presumably localized in the nuclear interior.

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An EDMD Mutation in C. elegans Lamin Blocks Muscle-Specific Gene Relocation and Compromises Muscle Integrity

Cited by 125 publications

References 52 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Cell Biology of the Caenorhabditis elegans Nucleus

Distinct features of lamin A-interacting chromatin domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin

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