Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence

Meuleman, Wouter; Peric-Hupkes, Daan; Kind, Jop; Beaudry, Jean–Bernard; Pagie, Ludo; Kellis, M; Reinders, Marcel J. T.; Wessels, Lodewyk F.A.; Steensel, Bas van

doi:10.1101/gr.141028.112

Cited by 386 publications

(547 citation statements)

References 45 publications

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“…The LINE-1-rich repeat array bordering the Dlk1-Dio3 imprinted cluster is nuclear lamina associated LINE-1s have been shown to be enriched in nuclear lamina-associated domains (LADs) (Meuleman et al 2013). Analysis of publicly available DamID profiles of LaminB association data confirms that the 227 kb LINE-rich insertion upstream of Dlk1 overlaps almost perfectly with a LAD in ES cell-derived neural precursor cells and astrocytes ( Fig.…”

Section: Characterization Of Line-1 Repeat Array In the Dlk1-dio3 Impmentioning

confidence: 80%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.

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Section: Characterization Of Line-1 Repeat Array In the Dlk1-dio3 Impmentioning

confidence: 80%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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“…LADs are A/T‐rich (Meuleman et al., 2013); hence, using a common genomic background (without a sequence bias) for both conditions to find motifs in lamin B1‐associated regions would not be appropriate. Thus, we compared sequences in lamin B1 domains against each other (young vs. old and old vs, young) to find motifs that were enriched in each condition.…”

Section: Resultsmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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“…3c). Furthermore, regions of facultative lamin-B1 association 32 are enriched in regions showing a reduction in compartment signal (from A to B-like), while those showing lamin-B1 association across different mouse cell lines are primarily B-type in both WT and the mutant (Extended Data Figure 9a, Methods ). Importantly, these changes in compartmentalization cannot be attributed to changes in expression or in the activity marks (H3K27ac, H3K4me3) that are largely unperturbed in the mutant at the scales relevant to compartmentalization (Extended Data Figures 8d,9b–e).…”

Section: Enhanced and Finer Compartmentalizationmentioning

confidence: 99%

Two independent modes of chromatin organization revealed by cohesin removal

Schwarzer

Abdennur

Goloborodko

et al. 2017

Nature

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Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-large active and inactive compartments, and partitioning into sub-megabase domains (TADs). Yet, it remains unclear how these layers of organization form, interact with one another and impact genome functions. Here, we show that deletion of the cohesin-loading factor Nipbl, in mouse liver, leads to a dramatic reorganization of chromosomal folding. TADs and associated peaks vanish globally, even in the absence of transcriptional changes. In contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the interplay of two independent mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; 2) cohesin-dependent formation of TADs, possibly by loop extrusion, which contributes to guide distant enhancers to their target genes.

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Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence

Cited by 386 publications

References 45 publications

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Two independent modes of chromatin organization revealed by cohesin removal

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