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An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

ABSTRACT: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

PROVIDER: PRJNA1204085 | ENA |

REPOSITORIES: ENA

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An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

Project description:Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset neurological disorder 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 result from genomic deletions upstream of the gene. However, recently identified families carrying the LMNB1 gene duplication, but lacking demyelination, have been found, suggesting the involvement of a non-coding regulatory element. To investigate this, a LMNB1-specific aCGH was conducted using DNA from these newly discovered families and canonical ADLD cases. This approach identified a genomic region, belonging to a silencer element, that is absent in ADLD cases with a LMNB1 duplication or deletion.

2024-12-29 | GSE285491 | GEO

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

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

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

| PRJNA997958 | ENA

Lamin B1 ChIPseq experiments from ER:RAS IMR90s

Project description:Lamin B1 from OIS IMR90s We used ChIP-seq to examine the global binding of Lamin B1 in human IMR90 oncogene-induced senescence

2014-12-15 | E-GEOD-53331 | biostudies-arrayexpress

Lamin B1 dependent transcriptional control in neural progenitor cells

Project description:Through knocking out Lamin B1, we found that lamin B1 regulets hundreds of genes in neural progenitor cells, which underlie differentiation of neural protenitor cells

2021-02-10 | GSE156156 | GEO

Lamin B1 ChIPseq experiments from ER:RAS IMR90s

Project description:Lamin B1 from OIS IMR90s

2014-12-15 | GSE53331 | GEO

Human lamin B1: stress-induced phosphorylation

Project description:This is a small scale study of the phosphorylation state of human lamin B1 immunoprecipitated from control cells or cells treated with methyl methane sulphonate (MMS, acting as a DNA damage stressor agent)

2017-05-30 | PXD006459 | Pride

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

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

| PRJNA561578 | ENA

Lamin B1 regulates somatic mutations and progression of B cell malignancies

Project description:Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B-cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B cell activation and formation of lymphoid germinal centres. ChIP-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNAi-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level was directly proportional to 5-year survival rate in chronic lymphocytic leukaemia, and was strongly involved in transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a "mutational gatekeeper", suppressing the aberrant mutations that drive lymphoid malignancy.

2017-08-03 | GSE89869 | GEO

Huntington’s disease as a lamin B1 nuclear envelopathy

Project description:Lamins, the major structural proteins within the nuclear lamina, are crucial for the functionality of cellular nucleus and their alterations are involved in the so-called laminopathies. We previously found that Huntington’s disease (HD), a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, courses with increased lamin B protein levels in specific brain regions in both mouse models and patients. We now show that these changes are mostly restricted to lamin B1, occur in striatal medium-sized spiny neurons and CA1 hippocampal neurons, and are accompanied by altered nuclear morphology, nucleocytoplasmic transport disruption and un-structuring of lamin-associated chromatin domains. Normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD results in beneficial restoring of nuclear lamina homeostasis and prevention of motor and cognitive dysfunction, opening a window for a new therapeutic approach for HD and other B1-type laminophaties.

2020-11-10 | GSE139884 | GEO

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