Gene regulatory loops at lamina-associated domains
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE221288 | GEO | 2023/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:The nuclear lamina is a proteinaceous network of filaments that provide both structural and gene regulatory functions by tethering proteins and large domains of DNA, so-called lamin associated domains (LADs), to the periphery of the nucleus. LADs are a large fraction of the mammalian genome that are repressed, in part, by their association to the nuclear periphery. The genesis and maintenance of LADs is poorly understood as are the proteins that participate in these functions. In an effort to identify proteins that reside at the nuclear periphery and potentially interact with LADs, we have taken a two-pronged approach. First, we have undertaken an interactome analysis of the inner nuclear membrane bound LAP2β to further characterize the nuclear lamina proteome. To accomplish this, we have leveraged the BioID system, which previously has been successfully used to characterize the nuclear lamina proteome. Second, we have established a system to identify proteins that bind to LADs by developing a chromatin directed BioID system. We combined the BioID system with the m6A-tracer system which binds to LADs in live cells to identify LAD proximal and nuclear lamina proteins. In combining these datasets, we have further characterized the protein network at the nuclear lamina as well as identified putative LAD proximal proteins. Our analysis identifies many heterochromatin related proteins related to H3K9 methylation processes as well as many proteins related to cell cycle regulation identifying important proteins essential for LAD function.
2021-03-09 | PXD012943 | Pride
Project description:A large fraction of the mammalian genome is organized into inactive chromosomal domains associated with the nuclear lamina. Using genomic repositioning assays we show that Lamina associated domains (LADs), spanning the developmentally regulated IgH and Cyp3a loci, contain transportable DNA regions that associate chromatin with the nuclear lamina and repress gene activity in fibroblasts. We characterized DNA regions within LADs that are functionally capable of positioning chromatin domains at the inner nuclear membrane (INM) lamina. We mapped and characterized the IgH and other LADs in murine fibroblasts. We show that these murine LADs have a unique chromatin structure with discrete boundaries. We demonstrate DNA regions within LADs that are capable of directing the association of chromatin domains with the INM-lamina as well as the silencing of a co-integrated reporter gene.
2012-02-24 | E-GEOD-36048 | biostudies-arrayexpress
Project description:Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confers structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains elusive, however. We examined changes in the association of lamin B1 with the genome in the first 72 hours of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. In addition, differentially expressed genes in LADs are linked to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation. We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment.
2022-03-21 | GSE185066 | GEO
Project description:Lamins are components of the peripheral nuclear lamina and interact with heterochromatic genomic regions, termed lamina-associated domains (LADs). In contrast to lamin B1, lamin A/C also localizes throughout the nucleus, where it associates with the chromatin-binding protein lamina-associated polypeptide (LAP) 2alpha. Here we show lamin A/C also interacts with euchromatin, as determined by chromatin immunoprecipitation analyses of eu- and heterochromatin-enriched samples. By way of contrast, lamin B1 was only found associated with heterochromatin. Euchromatic regions occupied by lamin A/C overlap with those bound by LAP2alpha, the depletion of which shifts binding of lamin A/C towards more heterochromatic regions. These alterations in lamin A/C chromatin interaction affect epigenetic histone marks in euchromatin without significantly affecting gene expression, while loss of lamin A/C in heterochromatic regions increased gene expression. Our data show a novel role of nucleoplasmic lamin A/C and LAP2alpha in regulating euchromatin. Examination of LaminA, LaminB and Lap2a DNA binding in Lap2alpha +/+ and Lap2a -/- cells and according changes in Histone modifications and gene expression
2016-01-19 | E-GEOD-70148 | biostudies-arrayexpress
Project description:Lamins are components of the peripheral nuclear lamina and interact with heterochromatic genomic regions, termed lamina-associated domains (LADs). In contrast to Lamin B11, lamin A/C also localizes throughout the nucleus, where it associates with the chromatin-binding protein lamina-associated polypeptide (LAP) 2alpha. Here we show lamin A/C also interacts with euchromatin, as determined by chromatin immunoprecipitation analyses of eu- and heterochromatin-enriched samples. By way of contrast, Lamin B11 was only found associated with heterochromatin. Euchromatic regions occupied by lamin A/C overlap with those bound by LAP2alpha, the depletion of which shifts binding of lamin A/C towards more heterochromatic regions. These alterations in lamin A/C chromatin interaction affect epigenetic histone marks in euchromatin without significantly affecting gene expression, while loss of lamin A/C in heterochromatic regions increased gene expression. Our data show a novel role of nucleoplasmic lamin A/C and LAP2alpha in regulating euchromatin. Examination of Lamin A/C, Lamin B1 and Lap2a DNA binding in Lap2alpha +/+ and Lap2a -/- cells and according changes in Histone modifications and gene expression
2016-01-19 | E-GEOD-70147 | biostudies-arrayexpress
Project description:The nuclear lamina (NL) interacts with hundreds of large genomic regions termed lamina-associated domains (LADs). The dynamics of these interactions and the relation to epigenetic modifications are poorly understood. We visualized the fate of LADs in single cells using a novel 'molecular contact memory' approach. In each interphase nucleus, only ~30% of LADs are positioned at the periphery; these LADs are in intermittent molecular contact with the NL but remain constrained to the periphery. Upon mitosis, LAD positioning is not detectably inherited but instead is stochastically reshuffled. Contact of individual LADs with the NL correlates with their degree of H3K9 dimethylation in single cells, and inactivation of the H3K9 methyltransferase G9a reduces the NL contact frequencies. These results indicate that nuclear positioning and histone modification of LADs are both stochastic yet linked in single cells. Collectively, these results highlight principles of the dynamic spatial architecture of chromosomes. LaminB1-chromatin interactions were assayed in human HT1080 cells by induction of Dam_LMNB1 expression in a stable cell line with shield1.
2013-01-31 | E-GEOD-40094 | biostudies-arrayexpress
Project description:Purpose: Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications and chromosomal interactions. We determined whether lamina-associated domains (LADs) display oscillatory circadian patterns of interaction with nuclear lamin B1 during hte circadian cycle, and identified any relationship to changes in gene expression patterns in oscillatory LADs or in their vinicity. Methods: To this end, we mapped LADs by chromatin immunoprecipitation-sequencing (ChIP-seq) of lamin B1 (LMNB1) (antibody ab16048, Abcam) from mouse livers colected every 6 h, for 30 h, after entrainment of the circadian clock by 24-h fasting and refeeding. Gene expression profiles were also analyzed by RNA-sequencing (RNA-seq) at the same time points. Results and Conclusions: We report periodic interactions of chromatin domains with nuclear lamin B1, suggesting rhythmic associations of fractions of the genome with the nuclear lamina. Entrainment of the circadian clock by fasting and refeeding is accompanied in mouse liver by a gain of lamin-chromatin interactions followed by oscillations in these interactions at hundreds of lamina-associated domains (LADs). A subset of these oscillations exhibit periodicity and affect one or both LAD borders or entire stand-alone LADs. Periodic LADs are however not a dominant feature of these variable LADs, as most LADs are conserved during the circadian cycle. LAD oscillations are for the most part asynchronous between the 5’ and 3’ ends of LADs. Periodic LADs also uncoupled from gene expression patterns, periodic or not, within or in vicinity of these LADs. Accordingly, periodic genes, including central clock-control genes, are located megabases away from LADs, suggesting their residence in a transcriptionally permissive environment throughout the circadian cycle. Our data suggest autonomous oscillatory associations of fractions of the genome with the nuclear lamina, providing new evidence for rhythmic spatial configurations of chromatin. However, our data also argue that periodic LADs constitute a minor fraction of variable LADs, and reflect stochasticity in variable lamin-chromatin interactions during the circadian cycle.
2019-08-20 | GSE128675 | GEO
Project description:A large fraction of the mammalian genome is organized into inactive chromosomal domains associated with the nuclear lamina. Using genomic repositioning assays we show that Lamina associated domains (LADs), spanning the developmentally regulated IgH and Cyp3a loci, contain transportable DNA regions that associate chromatin with the nuclear lamina and repress gene activity in fibroblasts.
2012-02-24 | GSE36048 | GEO
Project description:Mammalian interphase chromosomes interact with the nuclear lamina (NL) through hundreds of large Lamina Associated Domains (LADs). We report a method to map NL contacts genome-wide in single human cells. Analysis of ~400 maps reveals a core architecture of gene-poor LADs that contact the NL with high cell-to-cell consistency, interspersed by LADs with more variable NL interactions. The variable contacts are more sensitive to a change in genome ploidy than the consistent contacts. Single-cell maps indicate that NL contacts involve multivalent interactions over hundreds of kilobases. Moreover, we observe extensive intra-chromosomal coordination of NL contacts, even over tens of megabases. Such coordinated loci exhibit preferential interactions as detected by Hi-C. Finally, single-cell gene expression and chromatin accessibility analysis shows that loci with consistent NL contacts are expressed at lower levels and are more consistently inaccessible than loci with lower contact frequencies. These results highlight fundamental principles of single cell chromatin organization. Hi-C Data
2015-09-24 | E-GEOD-69841 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We have shown that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and upregulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here we test the hypothesis that change in expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2, uprregulation of lipid synthesis and storage, and culminating in steatosis in younger NAFLD patients (aged 21-51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlates with increased FOXA2 binding prior to severe steatosis in young mice placed on Western det. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and Lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.
2022-11-10 | GSE197399 | GEO