Lamina Associated Domains and Gene Regulation in Development and Cancer

Lochs, Silke J A; Kefalopoulou, Samy; Kind, Jop

doi:10.3390/cells8030271

Cited by 66 publications

(68 citation statements)

References 104 publications

(148 reference statements)

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“…These and previously reported data (Gonzalez-Sandoval & Gasser, 2016;van Steensel & Belmont, 2017;de Leeuw et al, 2018;Kim et al, 2019;Lochs et al, 2019) together suggest a balancing act between transcription and LADs: For many genes, LADs pose a repressive environment (Leemans et al, 2019). This, however, may be overcome by strong transcription activators.…”

Section: Discussionsupporting

confidence: 73%

“…In metazoan cell nuclei, large chromatin domains are associated with the nuclear lamina (NL) (Gonzalez-Sandoval & Gasser, 2016;van Steensel & Belmont, 2017;de Leeuw et al, 2018;Kim et al, 2019;Lochs et al, 2019). Mammalian genomes have roughly one thousand of such lamina-associated domains (LADs), which are typically hundreds of kb or even a few Mb in size.…”

Section: Introductionmentioning

confidence: 99%

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Local rewiring of genome–nuclear lamina interactions by transcription

et al. 2020

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Transcriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina‐associated domains (LADs). Activation of such genes is often accompanied by repositioning toward the nuclear interior. How this process works and how it impacts flanking chromosomal regions are poorly understood. We addressed these questions by systematic activation or inactivation of individual genes, followed by detailed genome‐wide analysis of NL interactions, replication timing, and transcription patterns. Gene activation inside LADs typically causes NL detachment of the entire transcription unit, but rarely more than 50–100 kb of flanking DNA, even when multiple neighboring genes are activated. The degree of detachment depends on the expression level and the length of the activated gene. Loss of NL interactions coincides with a switch from late to early replication timing, but the latter can involve longer stretches of DNA. Inactivation of active genes can lead to increased NL contacts. These extensive datasets are a resource for the analysis of LAD rewiring by transcription and reveal a remarkable flexibility of interphase chromosomes.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Local rewiring of genome–nuclear lamina interactions by transcription

et al. 2020

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“…In the past decade, DamID has been used to identify and characterize LADs [1,4,5,22]. However, conventional DamID lacks the temporal resolution needed to study dynamics of LAD -NL interactions that occur within time spans of about one hour.…”

Section: Discussionmentioning

confidence: 99%

“…LADs have a median size of ~0.5 Mb and jointly cover 30-50% of the genome. LADs are associated with gene repression and have been hypothesized to form a backbone for genome organization [2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Cell cycle dynamics of lamina associated DNA

Schaik

Vos

Peric-Hupkes

et al. 2019

Preprint

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words)In mammalian interphase nuclei more than one thousand large genomic regions are positioned at the nuclear lamina (NL). These lamina associated domains (LADs) are involved in gene regulation and may provide a backbone for the overall folding of interphase chromosomes. While LADs have been characterized in great detail, little is known about their dynamics during interphase, in particular at the onset of G1 phase and during DNA replication. To study these dynamics, we developed an antibody-based variant of the DamID technology (named pA-DamID) that allows us to map and visualize genome -NL interactions with high temporal resolution. Application of pA-DamID combined with synchronization and cell sorting experiments reveals that LAD -NL contacts are generally rapidly established early in G1 phase. However, LADs on the distal ~25 Mb of most chromosomes tend to contact the NL first and then gradually detach, while centromere-proximal LADs accumulate gradually at the NL. Furthermore, our data indicate that S-phase chromatin shows transiently increased lamin interactions. These findings highlight a dynamic choreography of LAD -NL contacts during interphase progression, and illustrate the usefulness of pA-DamID to study the dynamics of genome compartmentalization.genome-wide mapping of NL interactions, DamID has been the major method [1,22]. DamID is based on expression of a fusion protein of Dam and a NL protein (e.g. Lamin B1), which results in gradual accumulation of adenine methylation ( m6 A) on DNA that contacts the NL [23]. This m6 A labeled DNA is then amplified and sequenced. An added advantage of DamID is that the m6 A tags can be detected by a GFP-labeled m6 A-Tracer protein [8]. This enables visualization of LAD -NL contacts in situ, which greatly assists in the interpretation of genome-wide DamID mapping data.However, a major limitation of DamID is its poor temporal resolution. The activation of Dam and deposition of m6 A requires at least several hours [8,24], precluding detailed analysis of the NL interaction dynamics. To overcome these limitations, we developed pA-DamID -a hybrid of DamID and the CUT&RUN method [25]. This allows for both mapping and visualization of NL contacts with high temporal resolution. Using pA-DamID, we show that after mitosis NL contacts do not initiate at defined loci, but rather are widespread with an enrichment at LADs on distal regions of chromosomes. Furthermore, small LADs appear to be gradually displaced from the NL by larger LADs. Additionally, we found that replicating DNA shows transiently increasing lamin contacts. Results Principle of pA-DamID to map and visualize NL associated DNAThe pA-DamID method is a hybrid of the CUT&RUN and DamID technologies (Fig. 1A). In CUT&RUN, cells are permeabilized and incubated with an antibody against a nuclear protein of interest, followed by protein A (pA) fused to micrococcal nuclease (MNase). Subsequent activation of the tethered MNase by Ca ++ ions results in excision of DNA sequences that are in molecular proximity to the pro...

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“…Adjacent to the inner nuclear membrane, the nuclear lamina contacts peripheral chromatin through lamina-associated domains that generally repress gene expression, and lamin levels and localization may regulate chromatin organization and gene expression (Lochs et al, 2019;van Steensel and Belmont, 2017). Furthermore, Gene Set Enrichment Analysis identified chromatin/gene silencing and nucleosome assembly pathways as being upregulated in NTF2 high dox+ cells, consistent with the large number of downregulated genes in these cells.…”

Section: Ntf2 Levels Affect Lamin a Nuclear Localization Nuclear Sizmentioning

confidence: 60%

Nuclear Transport Factor 2 (NTF2) suppresses metastatic melanoma by modifying cell migration, metastasis, and gene expression

Vuković

White

Gigley

et al. 2020

Preprint

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While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression.We show that increasing NTF2 expression in metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and increases survival of mice. Mechanistically, we show that NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration. We propose that by decreasing nuclear size and/or lamin A nuclear localization, ectopic expression of NTF2 in metastatic melanoma alters chromatin organization to generate a gene expression profile with characteristics of primary melanoma, concomitantly abrogating several phenotypes associated with advanced stage cancer both in vitro and in vivo. Thus NTF2 acts as a melanoma tumor suppressor to maintain proper nuclear structure and gene expression and could be a novel therapeutic target to improve health outcomes of melanoma patients.

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Lamina Associated Domains and Gene Regulation in Development and Cancer

Cited by 66 publications

References 104 publications

Local rewiring of genome–nuclear lamina interactions by transcription

Local rewiring of genome–nuclear lamina interactions by transcription

Cell cycle dynamics of lamina associated DNA

Nuclear Transport Factor 2 (NTF2) suppresses metastatic melanoma by modifying cell migration, metastasis, and gene expression

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