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Comparative Genome-wide expression profiling of ADLD whole blood and fibroblasts cell lines.

ABSTRACT: Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by autonomic dysfunction, followed by cerebellar and pyramidal features. ADLD is caused by duplication of the lamin B1 gene (LMNB1), which leads to its increased expression. The molecular pathways involved in the disease are still poorly understood. Hence, we analyzed global gene expression in fibroblasts and whole blood of LMNB1 duplication carriers and used Gene Set Enrichment Analysis (GSEA) to explore their gene signatures. We found that LMNB1 duplication is associated with dysregulation of genes involved in the immune system, neuronal and skeletal development. Genes with an altered transcriptional profile clustered in specific genomic regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65368 | GEO | 2015/01/29

SECONDARY ACCESSION(S): PRJNA273810

REPOSITORIES: GEO

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Comparative Genome-wide expression profiling of ADLD whole blood and fibroblasts cell lines.

Project description:Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by autonomic dysfunction, followed by cerebellar and pyramidal features. ADLD is caused by duplication of the lamin B1 gene (LMNB1), which leads to its increased expression. The molecular pathways involved in the disease are still poorly understood. Hence, we analyzed global gene expression in fibroblasts and whole blood of LMNB1 duplication carriers and used Gene Set Enrichment Analysis (GSEA) to explore their gene signatures. We found that LMNB1 duplication is associated with dysregulation of genes involved in the immune system, neuronal and skeletal development. Genes with an altered transcriptional profile clustered in specific genomic regions. To identify altered pathways in ADLD, we performed a whole genome expression profiling on fibroblasts cell lines derived from 4 ADLD, 3 controls siblings, 2 age match controls, 2 uninvestigated samples; and from 4 ADLD whole blood, 8 controls siblings and 1 uninvestigated sample.

2015-01-29 | E-GEOD-65368 | biostudies-arrayexpress

Loss of an oligodendrocyte specific silencer element provides a framework to assess the pathogenic impact of lamin B1 structural variants

Project description:The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but that do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression only to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

2024-12-02 | GSE238093 | GEO

Redistribution of the Lamin B1 genomic binding profile affects spatial rearrangement of heterochromatic domains and gene expression during senescence

Project description:Senescence is a stress responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina, lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for H3K9me3. LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3, thus promoting SAHF formation, which is inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genomewide redistribution: firstly through the spatial re-organization of chromatin and, secondly, through gene repression. ChIP-seq for Lamin B1 in Growing and Ras Induced Senescence

2013-08-22 | E-GEOD-49341 | biostudies-arrayexpress

Lamin B1 deletion in myeloid neoplasms alters hematopoietic cell fate and causes Pelger-Huët nuclear anomaly

Project description:The most common cytogenetic abnormality found in complex karyotype high risk MDS/AML is del5q. Disease is often identified through visual inspection and recognition of abnormalities such as pseudo-Pelger-Huet anomaly (PPHA), which presents as deviations of normal neutrophil nuclear morphology. The link between PPHA and leukemia is unknown, but mutations in the lamin B1 receptor (LBR) have been identified as the cause of benign presence in otherwise normal individuals. Lamin B1 (LMNB1) is the ligand for LBR and is important for maintaining nuclear lamina integrity and influencing 3D gene structural changes that impact transcription; the LMNB1 gene locus is also contained with chromosome 5q, so we hypothesized that appearance of PPHA is potentially caused by del5q in MDS/AML containing the LMNB1. To help characterize the potential role of LMNB1 in normal hematopoietic stem and progenitor cells (HSPCs), we infected CD34+ cord blood HSPCs with lentiviruses expressing shRNAs targeting LMNB1 (LB1) and luciferase (C11) as a control and assessed changes in transcription due to LMNB1 disruption via RNSeq and 3D genome structural changes through HiC. Neutrophils were also differentiated from LMNB1 shRNA and control treated CD34+ cord blood HSPCs and transcriptional/structural changes identified via RNAseq and HiC. Additionally, to understand long-term in vivo effects of LMNB1 loss on self-renewal and lineage bias, we engrafted control and LMNB1 shRNA infected CD34+ HSPCs into NSG mice and harvest hCD34+ cells 12 weeks later for scRNAseq.

2022-03-11 | GSE174533 | GEO

Loss of lamin B1 results in prolongation of S-phase and decondensation of chromosome territories in the interphase nucleus of mammalian cells

Project description:Nuclear lamin B1 constitutes one of the major structural proteins in the lamina mesh. We silenced the expression of lamin B1 by RNA interference in the colon cancer cell line DLD-1 and showed a dramatic redistribution of H3K27me3 from the periphery to a more homogeneous nuclear dispersion; in addition we observed an increased frequency of micronuclei and nuclear blebs. By 3D-FISH analyses, we demonstrate that the volume and surface of chromosome territories were significantly larger in LMNB1-depleted cells, suggesting that lamin B1 is required to maintain chromatin condensation in interphase nuclei. These changes led to a prolonged S-phase due to activation of Chk1 and telomere attrition. Finally, silencing of LMNB1 resulted in extensive changes in alternative splicing of multiple genes and in a higher number of enlarged nuclear speckles. Taken together, our results suggest a mechanistic role of the nuclear lamina in the organization of chromosome territories, maintenance of genome integrity and proper gene splicing. This dataset includes the comparison of gene transcripts between cells with silenced lamin B1 and empty vector negative control transfected cells. Single cell clones were generated after transfection of DLD-1 cells with shRNA against LMNB1. Two different constructs were used. For clone number 2, three replicates of the the same clone were included in the analysis. The rest of the clones correspond to biological replicates. As control, we used three different cones transfected with an empty vector control as well as wild type cells.

2014-07-16 | E-GEOD-53546 | biostudies-arrayexpress

Redistribution of the Lamin B1 genomic binding profile affects spatial rearrangement of heterochromatic domains and gene expression during senescence

2013-08-22 | GSE49341 | GEO

Loss of lamin B1 results in prolongation of S-phase and decondensation of chromosome territories in the interphase nucleus of mammalian cells

2014-07-16 | GSE53546 | GEO

Differential features of lamina-associated domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin

Project description:The nuclear lamina interacts with the genome through megabase-size lamina-associated domains (LADs). LADs have been identified in proximity labeling assays and recently by chromatin immunoprecipitation-sequencing (ChIP-seq) of A- and B-type lamins. LADs localize mainly to the nuclear periphery, they are gene-poor and largely heterochromatic. Here, we show that the mode of chromatin fragmentation for ChIP, namely either bath sonication (used to date for ChIP of nuclear lamins) or digestion with micrococcal nuclease (MNase) leads to the discovery of distinct sets of lamin-interacting domains (which we refer to as LiDs) with distinct gene content, histone composition enrichment and relationship to lamin B1-interacting domains. We find that total genome coverage by lamin A/C ('LMNA') LiDs identified in sonicated or MNase-digested chromatin is similar (~730 megabases). Over half of these domains, however, are uniquely detected in sonicated or MNase-digested chromatin. Whereas sonication-specific LMNA LiDs are gene-poor and devoid of a broad panel of histone modifications, MNase-specific LMNA LiDs are of higher gene density and are enriched in H3K9me3, H3K27me3 and in histone variant H2A.Z. Analysis of published LMNB1 LADs and of LMNB1 LiDs identified by ChIP-seq further shows that LMNA can associate with 'open' chromatin domains displaying euchromatin features which are not associated with LMNB1. The differential genetic and epigenetic properties of lamin-interacting chromatin domains indicate the existence of distinct LiD populations identifiable in different chromatin contexts, including nuclease-accessible 'open' regions presumably localized in the nuclear interior.

2015-03-24 | GSE57149 | GEO

Molecular maps of the Lamin B1-associated genomic regions in oligodendrocyte lineage cells

Project description:This study addresses the mechanisms regulating the identity of oligodendrocyte progenitor cells (OPC) in physiological conditions and the pathological mechanisms leading to autosomal adrenoleukodystrophy (ADLD), a disease caused by persistence of lamin B1 (LMNB1) expression in oligodendrocytes (OL). Using mouse primary OPCs and a novel technique for the study of DNA-protein interaction, we identify the genomic regions showing dynamic interactions with LMNB1. The transition from ESC to OPC revealed increased association of gene involved in pluripotency and neuronal function and decreased association of gene categories associated with the differentiation of OPC into OL (including genes regulating epigenetic modifiers, RNA processing and protein phosphorylation). Since LMNB1 declines during the transition from OPC to OL, and its persistent expression has been linked to pathological conditions, such as ADLD, we further identified the molecular maps of genome-lamina reorganization in OPC differentiating into OL which continue to express LMNB1 (mOLLMNB1). The transition from OPC to mOLLMNB1 revealed increased association to LMNB1 of genomic regions encoding for lipid metabolism and protein phosphorylation, and decreased association of genes negatively regulating differentiation. These data highlight the importance of LMNB1 in physiological conditions and identify mechanisms responsible for late onset ADLD.

2020-03-16 | GSE135834 | GEO

Expression data from functional studies using RNAi on Lamin B1 in BL2 cells

Project description:Lamin B1 is a component of the nuclear envelope involved in epigenetic chromatin regulation and is reduced during B cell activation and formation of lymphoid germinal centres. RNAi-mediated reduction of Lamin B1 results in spontaneous SHM as well as kappa-light chain aberrant surface expression showing that Lamin B1 is a negative epigenetic regulator of SHM. We used Affymetrix Exon 1.0 ST microarrays to detail the global programme of gene expression underlying changes induced in siRNA-treated Lamin B1low BL2 cells. siRNA-mediated reduction of nuclear Lamin B1 incorporation resulted in a general upregulation of positive cell cycle regulatory genes which in turn occurred alongside an upregulation of genes responsible for cell cycle checkpoint execution or cell cycle arrest, and were specific for LMNB1 reduction.

2017-08-16 | GSE98529 | GEO

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