Deletions of Chromosome 7q Affect Nuclear Organization and HLXB9Gene Expression in Hematological Disorders

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.

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Abstract 508: Nuclear Lamins At Enhancers: A New Hypothesis for Laminopathies

Circulation Research ◽

10.1161/res.127.suppl_1.508 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Kohta Ikegami ◽

Stefano Secchia ◽

Omar Almakki ◽

Alexis V Stutzman ◽

Sachie Ikegami ◽

...

Keyword(s):

Gene Expression ◽

Histone Acetylation ◽

Binding Sites ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Lamin A ◽

New Paradigm ◽

Control Of Gene Expression ◽

Nuclear Lamins ◽

Nuclear Interior

The segregation of heterochromatin domains (LADs) at the nuclear periphery by the nuclear lamina, composed by polymerized nuclear Lamin A/C, provides a longstanding paradigm for the control of gene expression and for the mechanisms underlying Lamin-A/C-associated disorders, including progeria and cardiomyopathy. Here, we provide evidence supporting a novel paradigm that Lamin A/C functions as a transcription factor in the nuclear interior. We discovered that Ser22-phosphorylated Lamin A/C (pS22-Lamin A/C), required for lamin depolymerization during mitosis, populated the nuclear interior throughout the cell cycle. pS22-Lamin A/C ChIP-deq demonstrated localization at a large subset of putative active enhancers, not LADs. pS22-Lamin A/C-binding sites were co-occupied by the transcriptional activator c-Jun. In progeria patient-derived fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost whereas new pS22-Lamin A/C-binding sites emerged. New pS22-Lamin A/C binding was accompanied by increased histone acetylation and increased c-Jun binding, whereas loss of pS22-Lamin A/C-binding was accompanied by loss of histone acetylation and c-Jun binding. New pS22-Lamin A/C enhancer binding in progeria was associated with upregulated expression of genes implicated in progeria pathophysiology, including cardiovascular disease. In contrast, alteration of LADs in progeria-patient cells could not explain the observed gene expression changes. These results suggest that Lamin A/C regulates gene expression by enhancer binding in the nuclear interior, independent of its function at the nuclear lamina, providing a new paradigm for the pathogenesis of lamin-associated disorders. pS22-Lamin A/C was also present in the nuclear interior of adult mouse cardiomyocytes. Cardiomyocyte-specific deletion of Lmna encoding Lamin A/C in adult mice caused extensive transcriptional changes in the heart and dilated cardiomyopathy, without apparent reduction of nuclear peripheral Lamin A/C. Disruption of the gene regulatory rather than LAD tethering function of Lamin A/C may underlie the pathogenesis of disorders caused by LMNA mutations, including cardiomyopathy.

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Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes

Nature Communications ◽

10.1038/s41467-021-22331-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Bing He ◽

Ping Chen ◽

Sonia Zambrano ◽

Dina Dabaghie ◽

Yizhou Hu ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Human Kidney ◽

Cell Types ◽

Model Organisms ◽

Mural Cell ◽

Glomerular Cell ◽

Individual Gene ◽

The Individual

AbstractMolecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney. The analysis reveals genetic programs for all four glomerular cell types (podocytes, glomerular endothelial cells, MCs and PECs) as well as rare glomerulus-associated macula densa cells. Importantly, we detect heterogeneity in glomerulus-associated Pdgfrb-expressing cells, including bona fide intraglomerular MCs with the functionally active phagocytic molecular machinery, as well as a unique mural cell type located in the central stalk region of the glomerulus tuft. Furthermore, we observe remarkable species differences in the individual gene expression profiles of defined glomerular cell types that highlight translational challenges in the field and provide a guide to design translational studies.

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Representation of Individual Gene Expression in Completely Pooled mRNA Samples

Bioscience Biotechnology and Biochemistry ◽

10.1271/bbb.69.1098 ◽

2005 ◽

Vol 69 (6) ◽

pp. 1098-1103 ◽

Cited By ~ 8

Author(s):

Änne GLASS ◽

Jeannette HENNING ◽

Thomas KAROPKA ◽

Thomas SCHEEL ◽

Sven BANSEMER ◽

...

Keyword(s):

Gene Expression ◽

Individual Gene

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Abstract 195: Peripheral Blood S100A8 and S100A12 Gene Expression Correlate with Coronary Calcium Score and Percent Diameter Stenosis in Patients by CT-Angiography

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a195 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

James A Wingrove ◽

Michael R Elashoff ◽

Szilard Voros ◽

Gregory S Thomas ◽

Steven Rosenberg

Keyword(s):

Gene Expression ◽

Coronary Artery ◽

Ct Angiography ◽

Peripheral Blood ◽

Calcium Score ◽

Maximum Diameter ◽

Agatston Score ◽

Individual Gene ◽

Highly Correlated ◽

Whole Heart

Background— Coronary artery disease (CAD) can vary by coronary artery calcification (CAC) and extent of stenosis. A previously described peripheral blood 23-gene expression score (GES) was validated for discrimination of obstructive CAD and shown to correlate with maximum % diameter stenosis (%DS), however, its relation to CAC has not been analyzed in detail. S100A12, a component of the score, has been correlated with calcification in a transgenic mouse model. Methods— A total of 398 patients from the COMPASS trial ( NCT01117506 ) had both core-lab analyzed CT-angiography (CTA) and GES. CAC was determined as whole-heart Agatston score and per-patient maximum %DS by CTA. GES was measured by RT-PCR according to Corus CAD protocols (CardioDx, Palo Alto, CA). Individual gene expression levels were analyzed for significance relative to CAC and %DS by age and sex-adjusted logistic regression. Results— Patients were 50% male; 50/398 had obstructive CAD (≥50% stenosis by core-lab CTA). Both CAC and %DS were highly correlated with overall GES (p< 10-16). Genes significantly associated with %DS were expressed predominantly in either lymphocyte or myeloid cells (circles and squares in figure respectively, bottom quadrants) whereas no lymphocyte genes and a larger set of myeloid-specific genes were associated with CAC (squares in figure, left quadrants); S100A8 and S100A12 showed the strongest associations with CAC (p = 0.006). Conclusion— Gene expression significance for %DS appears to reflect increased neutrophil to lymphocyte ratio whereas neutrophil gene up-regulation appears correlated with CAC, the strongest association being seen with S100A8 and S100A12.

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Abstract 5953: Flow Pulsation Affect Distal Pulmonary Artery Endothelial Cell mRNA Expression

Circulation ◽

10.1161/circ.118.suppl_18.s_1037-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Min Li ◽

Kurt Stenmark ◽

Robin Shandas ◽

Wei Tan

Keyword(s):

Gene Expression ◽

Pulmonary Artery ◽

Pulsatile Flow ◽

Static Condition ◽

Flow Chamber ◽

Physical Characteristics ◽

List Type ◽

Flow Pulsation ◽

Individual Gene ◽

Speed Flow

Background: Due to the development of pulmonary arterial hypertension (PAH), distal pulmonary artery endothelial cells (dPAEC) are exposed to wall shear stress (SS) that is different in physical characteristics compared to normal condition. The effect of individual components of SS on PAEC biology has not been thoroughly examined. Thus the current study was designed to examine how dPAEC respond to different component of SS in regarding to gene expression including adhesion molecules: ICAM, VCAM, E-selectin; chemokine: MCP-1 and growth factors:VEGF, Flt-1. Methods: Bovine dPAEC were cultured and placed on fibronectin-coated slides till confluent. Cells were then exposed to SS with different frequency (1Hz, 2Hz), pulsation (low, medium and high with an average SS of 14 dynes/cm 2 ) and time (1hr or 6hrs). The flow studies were carried out using a flow chamber connected to a variable speed flow pump. All data was represented as fold change relative to static condition. Results: As shown in table below, The effect of flow frequency on gene expression depends on individual gene. There was no difference of ICAM expression between 1Hz and 2Hz. Frequency of 2Hz significantly increased VCAM and MCP-1 expression compared to frequency of 1Hz. Compared to static condition, steady flow increased all gene expression. One hour pulsatile flow further increased ICAM, VCAM, E-selectin and MCP-1 but not VEGF or Flt-1 expression as pulsation increased. 3) Prolonged pulsatile flow further increased all gene expression. Conclusion: Physical characteristics of flow, especially flow pulsation stimulate dPAEC gene expression which can contribute to the development of PAH.

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Glucose-Responsive Regulators of Gene Expression inSaccharomyces cerevisiaeFunction at the Nuclear Periphery via a Reverse Recruitment Mechanism

Genetics ◽

10.1534/genetics.106.068932 ◽

2007 ◽

Vol 175 (3) ◽

pp. 1127-1135 ◽

Cited By ~ 42

Author(s):

Nayan J. Sarma ◽

Terry M. Haley ◽

Kellie E. Barbara ◽

Thomas D. Buford ◽

Kristine A. Willis ◽

...

Keyword(s):

Gene Expression ◽

Nuclear Periphery ◽

Reverse Recruitment

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Collaborative Cross Founder Expression Analysis (CCFEA)

10.1101/2021.03.04.422591 ◽

2021 ◽

Author(s):

Richard R Green ◽

Renee C Ireton ◽

Martin Ferris ◽

Kathleen Muenzen ◽

David R Crosslin ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Gene Expression Data ◽

Viral Infections ◽

Collaborative Cross ◽

Visualization Tool ◽

Expression Data ◽

Individual Gene ◽

Rnaseq Data

To understand the role of genetic variation in SARS and Influenza infections we developed CCFEA, a shiny visualization tool using public RNAseq data from the collaborative cross (CC) founder strains (A/J, C57BL/6J, 129s1/SvImJ, NOD/ShILtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Individual gene expression data is displayed across founders, viral infections and days post infection.

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H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

eLife ◽

10.7554/elife.49278 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Andrey Poleshko ◽

Cheryl L Smith ◽

Son C Nguyen ◽

Priya Sivaramakrishnan ◽

Karen G Wong ◽

...

Keyword(s):

Cell Division ◽

Spatial Organization ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Positional Information ◽

Specific Gene ◽

Cell Type ◽

Histone 3 ◽

Spatial Positioning ◽

Peripheral Heterochromatin

Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression and identity. Here we show that histone 3 lysine 9 dimethylation (H3K9me2) is an evolutionarily conserved, specific mark of nuclear peripheral heterochromatin and that it is retained through mitosis. During mitosis, phosphorylation of histone 3 serine 10 temporarily shields the H3K9me2 mark allowing for dissociation of chromatin from the nuclear lamina. Using high-resolution 3D immuno-oligoFISH, we demonstrate that H3K9me2-enriched genomic regions, which are positioned at the nuclear lamina in interphase cells prior to mitosis, re-associate with the forming nuclear lamina before mitotic exit. The H3K9me2 modification of peripheral heterochromatin ensures that positional information is safeguarded through cell division such that individual LADs are re-established at the nuclear periphery in daughter nuclei. Thus, H3K9me2 acts as a 3D architectural mitotic guidepost. Our data establish a mechanism for epigenetic memory and inheritance of spatial organization of the genome.

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Biological Image Analysis via Matrix Approximation

Encyclopedia of Data Warehousing and Mining, Second Edition ◽

10.4018/978-1-60566-010-3.ch027 ◽

2011 ◽

pp. 166-170

Author(s):

Jieping Ye ◽

Ravi Janardan ◽

Sudhir Kumar

Keyword(s):

Gene Expression ◽

Expression Pattern ◽

Expression Patterns ◽

Gene Expression Pattern ◽

Controlled Vocabulary ◽

Gene Expression Patterns ◽

Image Content ◽

Gene Expressions ◽

Microarray Gene Expression ◽

Individual Gene

Understanding the roles of genes and their interactions is one of the central challenges in genome research. One popular approach is based on the analysis of microarray gene expression data (Golub et al., 1999; White, et al., 1999; Oshlack et al., 2007). By their very nature, these data often do not capture spatial patterns of individual gene expressions, which is accomplished by direct visualization of the presence or absence of gene products (mRNA or protein) (e.g., Tomancak et al., 2002; Christiansen et al., 2006). For instance, the gene expression pattern images of a Drosophila melanogaster embryo capture the spatial and temporal distribution of gene expression patterns at a given developmental stage (Bownes, 1975; Tsai et al., 1998; Myasnikova et al., 2002; Harmon et al., 2007). The identification of genes showing spatial overlaps in their expression patterns is fundamentally important to formulating and testing gene interaction hypotheses (Kumar et al., 2002; Tomancak et al., 2002; Gurunathan et al., 2004; Peng & Myers, 2004; Pan et al., 2006). Recent high-throughput experiments of Drosophila have produced over fifty thousand images (http://www. fruitfly.org/cgi-bin/ex/insitu.pl). It is thus desirable to design efficient computational approaches that can automatically retrieve images with overlapping expression patterns. There are two primary ways of accomplishing this task. In one approach, gene expression patterns are described using a controlled vocabulary, and images containing overlapping patterns are found based on the similarity of textual annotations. In the second approach, the most similar expression patterns are identified by a direct comparison of image content, emulating the visual inspection carried out by biologists [(Kumar et al., 2002); see also www.flyexpress.net]. The direct comparison of image content is expected to be complementary to, and more powerful than, the controlled vocabulary approach, because it is unlikely that all attributes of an expression pattern can be completely captured via textual descriptions. Hence, to facilitate the efficient and widespread use of such datasets, there is a significant need for sophisticated, high-performance, informatics-based solutions for the analysis of large collections of biological images.

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Histone H3K9 methylation promotes formation of genome compartments inCaenorhabditis elegansvia chromosome compaction and perinuclear anchoring

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2002068117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11459-11470 ◽

Cited By ~ 1

Author(s):

Qian Bian ◽

Erika C. Anderson ◽

Qiming Yang ◽

Barbara J. Meyer

Keyword(s):

Gene Expression ◽

Nuclear Periphery ◽

Chromosome Conformation ◽

C Elegans ◽

Genome Wide ◽

Central Regions ◽

In Trans ◽

Genomic Regions ◽

In Cis ◽

Gene Expression Levels

Genomic regions preferentially associate with regions of similar transcriptional activity, partitioning genomes into active and inactive compartments within the nucleus. Here we explore mechanisms controlling genome compartment organization inCaenorhabditis elegansand investigate roles for compartments in regulating gene expression. Distal arms ofC. eleganschromosomes, which are enriched for heterochromatic histone modifications H3K9me1/me2/me3, interact with each other bothin cisandin trans,while interacting less frequently with central regions, leading to genome compartmentalization. Arms are anchored to the nuclear periphery via the nuclear envelope protein CEC-4, which binds to H3K9me. By performing genome-wide chromosome conformation capture experiments (Hi-C), we showed that eliminating H3K9me1/me2/me3 through mutations in the methyltransferase genesmet-2andset-25significantly impaired formation of inactive Arm and active Center compartments.cec-4mutations also impaired compartmentalization, but to a lesser extent. We found that H3K9me promotes compartmentalization through two distinct mechanisms: Perinuclear anchoring of chromosome arms via CEC-4 to promote theircisassociation, and an anchoring-independent mechanism that compacts individual chromosome arms. In bothmet-2 set-25andcec-4mutants, no dramatic changes in gene expression were found for genes that switched compartments or for genes that remained in their original compartment, suggesting that compartment strength does not dictate gene-expression levels. Furthermore, H3K9me, but not perinuclear anchoring, also contributes to formation of another prominent feature of chromosome organization, megabase-scale topologically associating domains on X established by the dosage compensation condensin complex. Our results demonstrate that H3K9me plays crucial roles in regulating genome organization at multiple levels.

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