Enhancers on the edge - how the nuclear envelope controls gene regulatory elements.

Precise temporal and sequential control of gene expression during development and in response to environmental stimuli requires tight regulation of the physical contact between gene regulatory elements and promoters. Current models describing how the genome folds in 3D space to establish these interactions often ignore the role of the most stable structural nuclear feature - the nuclear envelope. While contributions of 3D folding within/between topologically associated domains (TADs) have been extensively described, mechanical contributions from the nuclear envelope can impact enhancer-promoter interactions both directly and indirectly through influencing intra/inter-TAD interactions.

Reduction in Nuclear Size by DHRS7 in Prostate Cancer Cells and by Estradiol Propionate in DHRS7-Depleted Cells.

Increased nuclear size correlates with lower survival rates and higher grades for prostate cancer. The short-chain dehydrogenase/reductase (SDR) family member DHRS7 was suggested as a biomarker for use in prostate cancer grading because it is largely lost in higher-grade tumors. Here, we found that reduction in DHRS7 from the LNCaP prostate cancer cell line with normally high levels of DHRS7 increases nuclear size, potentially explaining the nuclear size increase observed in higher-grade prostate tumors where it is lost.

Nuclear size rectification: A potential new therapeutic approach to reduce metastasis in cancer.

Research on metastasis has recently regained considerable interest with the hope that single cell technologies might reveal the most critical changes that support tumor spread. However, it is possible that part of the answer has been visible through the microscope for close to 200 years. Changes in nuclear size characteristically occur in many cancer types when the cells metastasize.

Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees.

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes to find its pathomechanism were unavailing, so we engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in seven genes.

MALDI mass spectrometry imaging workflow for the aquatic model organisms Danio rerio and Daphnia magna.

Lipids play various essential roles in the physiology of animals. They are also highly dependent on cellular metabolism or status. It is therefore crucial to understand to which extent animals can stabilize their lipid composition in the presence of external stressors, such as chemicals that are released into the environment.

The Cytogenetic Landscape of Pediatric Chronic Myeloid Leukemia Diagnosed in Chronic Phase.

Philadelphia chromosome-positive chronic myeloid leukemia (CML) is cytogenetically characterized by the classic translocation t(9;22)(q34;q11), whereas additional non-Philadelphia aberrations (nPhAs) have been studied extensively in adult patients with CML, knowledge on nPhAs in pediatric patients with CML is still sparse. Here, we have determined nPhAs in a cohort of 161 patients younger than 18 years diagnosed with chronic phase CML and consecutively enrolled in the German national CML-PAED-II registry. In 150 cases (93%), an informative cytogenetic analysis had been performed at diagnosis.

Chemical Interrogation of Nuclear Size Identifies Compounds with Cancer Cell Line-Specific Effects on Migration and Invasion.

: Lower survival rates for many cancer types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific manner. Hypothesizing that such changes might confer an advantage to tumor cells, we aimed at the identification of commercially available compounds to guide further mechanistic studies. We therefore screened for Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved compounds that reverse the direction of characteristic tumor nuclear size changes in PC3, HCT116, and H1299 cell lines reflecting, respectively, prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer.

Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy.

Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior.

Classification of target tissues of Eisenia fetida using sequential multimodal chemical analysis and machine learning.

Acquiring comprehensive knowledge about the uptake of pollutants, impact on tissue integrity and the effects at the molecular level in organisms is of increasing interest due to the environmental exposure to numerous contaminants. The analysis of tissues can be performed by histological examination, which is still time-consuming and restricted to target-specific staining methods. The histological approaches can be complemented with chemical imaging analysis.

STING nuclear partners contribute to innate immune signaling responses.

STimulator of INterferon Genes (STING) is an adaptor for cytoplasmic DNA sensing by cGAMP/cGAS that helps trigger innate immune responses (IIRs). Although STING is mostly localized in the ER, we find a separate inner nuclear membrane pool of STING that increases mobility and redistributes to the outer nuclear membrane upon IIR stimulation by transfected dsDNA or dsRNA mimic poly(I:C). Immunoprecipitation of STING from isolated nuclear envelopes coupled with mass spectrometry revealed a distinct nuclear envelope-STING proteome consisting of known nuclear membrane proteins and enriched in DNA- and RNA-binding proteins.

Bisphenols exert detrimental effects on neuronal signaling in mature vertebrate brains.

Bisphenols are important plasticizers currently in use and are released at rates of hundreds of tons each year into the biosphere. However, for any bisphenol it is completely unknown if and how it affects the intact adult brain, whose powerful homeostatic mechanisms could potentially compensate any effects bisphenols might have on isolated neurons. Here we analyzed the effects of one month of exposition to BPA or BPS on an identified neuron in the vertebrate brain, using intracellular in vivo recordings in the uniquely suited Mauthner neuron in goldfish.

Paediatric chronic myeloid leukaemia presenting in de novo or secondary blast phase - a comparison of clinical and genetic characteristics.

Additional data on blast phase (BP) chronic myeloid leukaemia (CML) in children and adolescents is essential for improving diagnostic and therapeutic approaches of this rare but serious condition. Here, we describe distinct clinical and genetic characteristics of 18 paediatric patients with de novo (n = 10) and secondary (n = 8) BP CML enrolled in the CML-PAED-II trial and registry. Our findings suggest that paediatric patients exhibit a diverse cytogenetic profile compared to adults with BP CML.

Disruption Alters Radial Gene Positioning in Mouse Liver Leading to Metabolic Defects and Diabetes Characteristics.

Tissue-specific patterns of radial genome organization contribute to genome regulation and can be established by nuclear envelope proteins. Studies in this area often use cancer cell lines, and it is unclear how well such systems recapitulate genome organization of primary cells or animal tissues; so, we sought to investigate radial genome organization in primary liver tissue hepatocytes. Here, we have used a liver model to show that manipulating one of these nuclear membrane proteins is sufficient to alter tissue-specific gene positioning and expression.

Biochemical parameters and nutritional status of surgical patients with gastrointestinal cancer: a literature review.

This is an integrative literature review with the objective of identifying the relationship between biochemical parameters and the nutritional status of surgical patients with cancer of the gastrointestinal tract, developed in April 2019, encompassing the databases SCOPUS (Elsevier), PubMed Central® (PMC), and the Cochrane Virtual Health Library (BVS). We used the terms "Gastrointestinal Neoplasm" AND "Nutritional Status" AND "Blood Chemical Analysis" with the aid of the Academical software after the protocol validation. Out of 147 articles analyzed, seven were included in the review, as they met the inclusion criteria.

The NEMP family supports metazoan fertility and nuclear envelope stiffness.

Human genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in () with early menopause; however, it is unclear whether NEMP1 has any role in fertility. We show that whole-animal loss of NEMP1 homologs in , , zebrafish, and mice leads to sterility or early loss of fertility. Loss of Nemp leads to nuclear shaping defects, most prominently in the germ line.

Nucleoplasmic signals promote directed transmembrane protein import simultaneously via multiple channels of nuclear pores.

Roughly 10% of eukaryotic transmembrane proteins are found on the nuclear membrane, yet how such proteins target and translocate to the nucleus remains in dispute. Most models propose transport through the nuclear pore complexes, but a central outstanding question is whether transit occurs through their central or peripheral channels. Using live-cell high-speed super-resolution single-molecule microscopy we could distinguish protein translocation through the central and peripheral channels, finding that most inner nuclear membrane proteins use only the peripheral channels, but some apparently extend intrinsically disordered domains containing nuclear localization signals into the central channel for directed nuclear transport.

A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism.

Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation.

Casting a Wider Net: Differentiating between Inner Nuclear Envelope and Outer Nuclear Envelope Transmembrane Proteins.

The nuclear envelope (NE) surrounds the nucleus with a double membrane in eukaryotic cells. The double membranes are embedded with proteins that are synthesized on the endoplasmic reticulum and often destined specifically for either the outer nuclear membrane (ONM) or the inner nuclear membrane (INM). These nuclear envelope transmembrane proteins (NETs) play important roles in cellular function and participate in transcription, epigenetics, splicing, DNA replication, genome architecture, nuclear structure, nuclear stability, nuclear organization, and nuclear positioning.

Lamin A molecular compression and sliding as mechanisms behind nucleoskeleton elasticity.

Lamin A is a nuclear intermediate filament protein critical for nuclear architecture and mechanics and mutated in a wide range of human diseases. Yet little is known about the molecular architecture of lamins and mechanisms of their assembly. Here we use SILAC cross-linking mass spectrometry to determine interactions within lamin dimers and between dimers in higher-order polymers.

The cell-wide web coordinates cellular processes by directing site-specific Ca flux across cytoplasmic nanocourses.

Ca coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca diffusion and by nanocourse-specific Ca-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca ATPase 2b (SERCA2b).

Spatial Genome Organization: From Development to Disease.

Every living organism, from bacteria to humans, contains DNA encoding anything from a few hundred genes in intracellular parasites such as , up to several tens of thousands in many higher organisms. The first observations indicating that the nucleus had some kind of organization were made over a hundred years ago. Understanding of its significance is both limited and aided by the development of techniques, in particular electron microscopy, fluorescence hybridization, DamID and most recently HiC.