Closing the (nuclear) envelope on the genome: How nuclear lamins interact with promoters and modulate gene expression

Collas, Philippe; Lund, Eivind; Oldenburg, Anja R.

doi:10.1002/bies.201300138

Cited by 45 publications

(42 citation statements)

References 98 publications

(191 reference statements)

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“…1 Interactions of nuclear lamins with chromatin occur through large genomic areas of »0.1-10 megabases (mb). These domains have been termed lamina-associated domains (LADs) with the implication that lamins associate with chromatin only at the nuclear lamina, that is, at the nuclear periphery [2][3][4][5] (reviewed in [6][7][8] ). LADs have initially been discovered by DamID (DNA adenine methyltransferase [Dam] identification, a proximity assay).…”

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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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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“…Epigenetic gene silencing can be divided into three processes: initiation of gene silencing, maintenance of the repressive chromatin state, and inheritance through S-phase and mitosis 4 , 9 , 10 . In addition to these processes, recent studies have demonstrated the functional importance of spatial chromatin organization in epigenetic control 11 , 12 …”

Section: Introductionmentioning

confidence: 99%

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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“…In addition, lamins have been shown to play important roles in many essential cellular functions, including gene expression, DNA replication, DNA repair, chromatin organization, cell proliferation and differentiation, cell signaling, and cell division (Dechat et al 2008;Zuela et al 2012;Burke and Stewart 2013;Choi and Worman 2014;Collas et al 2014;Kennedy and Pennypacker 2014;Shimi and Goldman 2014). Despite all of their important functions, recent studies showed that lamins are not required for the proliferation and differentiation of ESCs and the proliferation of mouse embryonic fibroblasts and keratinocytes but seem to be important for later developmental processes, including tissue formation and homeostasis and organogenesis (Kim et al 2011Jung et al 2014).…”

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confidence: 99%

Lamins at the crossroads of mechanosignaling

2015

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The intermediate filament proteins, A-and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a ''mechanostat'' that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced ''inside-out signaling'' through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues.

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Closing the (nuclear) envelope on the genome: How nuclear lamins interact with promoters and modulate gene expression

Cited by 45 publications

References 98 publications

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

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

Human factors and pathways essential for mediating epigenetic gene silencing

Lamins at the crossroads of mechanosignaling

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