Effects of Fluctuation of Chromosome Conformation and Spatial Arrangement of Genes on the Pattern of Gene Expression

Tissue-specific gene expression is thought to be one of the major forces shaping mammalian gene order. A recent study that used whole-genome chromosome conformation assays has shown that the mammalian genome is divided into specific topological domains that are shared between different tissues and organisms. Here, we wanted to assess whether gene expression and regulation are involved in shaping these domains and can be used to classify them. We analyzed gene expression and regulation levels in these domains by using RNA-seq and enhancer-associated ChIP-seq datasets for 17 different mouse tissues. We found 162 domains that are active (high gene expression and regulation) in all 17 tissues. These domains are significantly shorter, contain less repeats, and have more housekeeping genes. In contrast, we found 29 domains that are inactive (low gene expression and regulation) in all analyzed tissues and are significantly longer, have more repeats, and gene deserts. Tissue-specific active domains showed some correlation with tissue-type and gene ontology. Domain temporal gene regulation and expression differences also displayed some gene ontology terms fitting their temporal function. Combined, our results provide a catalog of shared and tissue-specific topological domains and suggest that gene expression and regulation could have a role in shaping them.

Download Full-text

Chromatin interaction aware gene regulatory modeling with graph attention networks

10.1101/2021.03.31.437978 ◽

2021 ◽

Author(s):

Alireza Karbalayghareh ◽

Merve Sahin ◽

Christina S Leslie

Keyword(s):

Gene Expression ◽

Deep Learning ◽

Chromatin Interaction ◽

Learning Approach ◽

Chromosome Conformation ◽

Attention Networks ◽

Current State ◽

Regulatory Impact ◽

Sequence Elements ◽

Gene Expression Levels

Linking distal enhancers to genes and modeling their impact on target gene expression are longstanding unresolved problems in regulatory genomics and critical for interpreting non-coding genetic variation. Here we present a new deep learning approach called GraphReg that exploits 3D interactions from chromosome conformation capture assays in order to predict gene expression from 1D epigenomic data or genomic DNA sequence. By using graph attention networks to exploit the connectivity of distal elements and promoters, GraphReg more faithfully models gene regulation and more accurately predicts gene expression levels than dilated convolutional neural networks (CNNs), the current state-of-the-art deep learning approach for this task. Feature attribution used with GraphReg accurately identifies functional enhancers of genes, as validated by CRISPRi-FlowFISH and TAP-seq assays, outperforming both CNNs and the recently proposed Activity-by-Contact model. GraphReg therefore represents an important advance in modeling the regulatory impact of epigenomic and sequence elements.

Download Full-text

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.

Download Full-text

Genome Improvement and Core Gene Set Refinement of Fugacium kawagutii

Microorganisms ◽

10.3390/microorganisms8010102 ◽

2020 ◽

Vol 8 (1) ◽

pp. 102 ◽

Cited By ~ 3

Author(s):

Tangcheng Li ◽

Liying Yu ◽

Bo Song ◽

Yue Song ◽

Ling Li ◽

...

Keyword(s):

Gene Expression ◽

Gene Annotation ◽

Gene Prediction ◽

Acid Synthesis ◽

Core Gene ◽

Chromosome Conformation ◽

Gene Set ◽

Kegg Pathways ◽

Expression Studies ◽

Gene Expression Studies

Cataloging an accurate functional gene set for the Symbiodiniaceae species is crucial for addressing biological questions of dinoflagellate symbiosis with corals and other invertebrates. To improve the gene models of Fugacium kawagutii, we conducted high-throughput chromosome conformation capture (Hi-C) for the genome and Illumina combined with PacBio sequencing for the transcriptome to achieve a new genome assembly and gene prediction. A 0.937-Gbp assembly of F. kawagutii were obtained, with a N50 > 13 Mbp and the longest scaffold of 121 Mbp capped with telomere motif at both ends. Gene annotation produced 45,192 protein-coding genes, among which, 11,984 are new compared to previous versions of the genome. The newly identified genes are mainly enriched in 38 KEGG pathways including N-Glycan biosynthesis, mRNA surveillance pathway, cell cycle, autophagy, mitophagy, and fatty acid synthesis, which are important for symbiosis, nutrition, and reproduction. The newly identified genes also included those encoding O-methyltransferase (O-MT), 3-dehydroquinate synthase, homologous-pairing protein 2-like (HOP2) and meiosis protein 2 (MEI2), which function in mycosporine-like amino acids (MAAs) biosynthesis and sexual reproduction, respectively. The improved version of the gene set (Fugka_Geneset _V3) raised transcriptomic read mapping rate from 33% to 54% and BUSCO match from 29% to 55%. Further differential gene expression analysis yielded a set of stably expressed genes under variable trace metal conditions, of which 115 with annotated functions have recently been found to be stably expressed under three other conditions, thus further developing the “core gene set” of F. kawagutii. This improved genome will prove useful for future Symbiodiniaceae transcriptomic, gene structure, and gene expression studies, and the refined “core gene set” will be a valuable resource from which to develop reference genes for gene expression studies.

Download Full-text

Exposure to Gestational Diabetes Enriches Immune-Related Pathways in the Transcriptome and Methylome of Human Amniocytes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa466 ◽

2020 ◽

Vol 105 (10) ◽

pp. 3250-3264 ◽

Cited By ~ 1

Author(s):

Sara E Pinney ◽

Apoorva Joshi ◽

Victoria Yin ◽

So Won Min ◽

Cetewayo Rashid ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Gestational Diabetes ◽

Gestational Age ◽

In Utero ◽

Interferon Response ◽

Metabolic Dysfunction ◽

Chromosome Conformation ◽

Obesity And Diabetes ◽

Genome Wide

Abstract Context Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu and is linked to obesity and diabetes in offspring, but the mechanisms driving these effects remain largely unknown. Alterations in DNA methylation and gene expression in amniocytes exposed to GDM in utero represent a potential mechanism leading to metabolic dysfunction later in life. Objective To profile changes in genome-wide DNA methylation and expression in human amniocytes exposed to GDM. Design A nested case-control study (n = 14 pairs) was performed in amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis, and gestational age at birth. Sex-specific genome-wide DNA methylation analysis and RNA-sequencing were completed and differentially methylated regions (DMRs) and gene expression changes were identified. Ingenuity pathway analysis identified biologically relevant pathways enriched after GDM exposure. In silico high-throughput chromosome conformation capture (Hi-C) analysis identified potential chromatin interactions with DMRs. Results Expression of interferon-stimulated genes was increased in GDM amniocytes, accounting for 6 of the top 10 altered genes (q < 0.05). Enriched biological pathways in GDM amniocytes included pathways involving inflammation, the interferon response, fatty liver disease, monogenic diabetes, and atherosclerosis. Forty-two DMRs were identified in male GDM-exposed amniocytes and 20 in female amniocyte analysis (q < 0.05). Hi-C analysis identified interactions between DMRs and 11 genes with significant expression changes in male amniocytes and 9 in female amniocytes (P < .05). Conclusion In a unique repository of human amniocytes exposed to GDM in utero, transcriptome analysis identified enrichment of inflammation and interferon-related pathways and novel DMRs with potential distal regulatory functions.

Download Full-text

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers

Nucleus ◽

10.1080/19491034.2017.1280209 ◽

2017 ◽

Vol 8 (4) ◽

pp. 383-391 ◽

Cited By ~ 8

Author(s):

Haiming Chen ◽

Laura Seaman ◽

Sijia Liu ◽

Thomas Ried ◽

Indika Rajapakse

Keyword(s):

Gene Expression ◽

Human Fibroblasts ◽

Expression Patterns ◽

Gene Expression Patterns ◽

Chromosome Conformation

Download Full-text

Cohesin disrupts polycomb-dependent chromosome interactions

10.1101/593970 ◽

2019 ◽

Cited By ~ 6

Author(s):

JDP Rhodes ◽

A Feldmann ◽

B Hernández-Rodríguez ◽

N Díaz ◽

JM Brown ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

Gene Repression ◽

Chromosome Conformation ◽

Regulate Gene Expression ◽

Topologically Associating Domains ◽

Chromosome Organisation ◽

Regulate Gene

AbstractHow chromosome organisation is related to genome function remains poorly understood. Cohesin, loop-extrusion, and CTCF have been proposed to create structures called topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find as in other cell types that cohesin is required to create TADs and regulate A/B compartmentalisation. However, in the absence of cohesin we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system, depend on PRC1, and we discover that cohesin counteracts these interactions. This disruptive activity is independent of CTCF and TADs, and regulates gene repression by the polycomb system. Therefore, in contrast to the proposal that cohesin creates structure in chromosomes, we discover a new role for cohesin in disrupting polycomb-dependent chromosome interactions to regulate gene expression.

Download Full-text

Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

10.1101/555250 ◽

2019 ◽

Cited By ~ 1

Author(s):

Alessandro Bertero ◽

Paul A. Fields ◽

Alec S. T. Smith ◽

Andrea Leonard ◽

Kevin Beussman ◽

...

Keyword(s):

Gene Expression ◽

Large Scale ◽

Induced Pluripotent Stem Cell ◽

Lamin A ◽

Chromosome Conformation ◽

Human Cardiomyocytes ◽

Nuclear Lamins ◽

Genome Wide ◽

Induced Pluripotent ◽

Gene Expression Alterations

AbstractPathogenic mutations in A-type nuclear lamins cause dilated cardiomyopathy, which is postulated to result from dysregulated gene expression due to changes in chromatin organization into active and inactive compartments. To test this, we performed genome-wide chromosome conformation analyses (Hi-C) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a haploinsufficient mutation for lamin A/C. Compared to gene-corrected cells, mutant hiPSC-CMs have marked electrophysiological and contractile alterations, with modest gene expression changes. While large-scale changes in chromosomal topology are evident, differences in chromatin compartmentalization are limited to a few hotspots that escape inactivation during cardiogenesis. These regions exhibit upregulation of multiple non-cardiac genes including CACNA1A, encoding for neuronal P/Q-type calcium channels. Pharmacological inhibition of the resulting current partially mitigates the electrical alterations. On the other hand, A/B compartment changes do not explain most gene expression alterations in mutant hiPSC-CMs. We conclude that global errors in chromosomal compartmentation are not the primary pathogenic mechanism in heart failure due to lamin A/C haploinsufficiency.SummaryBertero et al. observe that lamin A/C haploinsufficiency in human cardiomyocytes markedly alters electrophysiology, contractility, gene expression, and chromosomal topology. Contrary to expectations, however, changes in chromatin compartments involve just few regions, and most dysregulated genes lie outside these hotspots.Condensed titleGenomic effects of lamin A/C haploinsufficiency

Download Full-text

Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence

PLoS Genetics ◽

10.1371/journal.pgen.1008603 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1008603

Author(s):

Tina Wagner ◽

Lara Pérez-Martínez ◽

René Schellhaas ◽

Marta Barrientos-Moreno ◽

Merve Öztürk ◽

...

Keyword(s):

Homologous Recombination ◽

Short Distance ◽

Replicative Senescence ◽

Spatial Arrangement ◽

Short Telomere ◽

Chromosome Conformation ◽

Protein Levels ◽

Histone Modifiers ◽

Yeast Telomere ◽

Subtelomeric Regions

Telomeres have the ability to adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomere chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a distinct telomeric chromatin environment is a major requirement for the folding of yeast telomeres. We demonstrate that telomeres are not folded when cells enter replicative senescence, which occurs independently of short telomere length. Indeed, Sir2, Sin3 and Set2 protein levels are decreased during senescence and their absence may thereby prevent telomere folding. Additionally, we show that the homologous recombination machinery, including the Rad51 and Rad52 proteins, as well as the checkpoint component Rad53 are essential for establishing the telomere fold-back structure. This study outlines a method to interrogate telomere-subtelomere interactions at a single unmodified yeast telomere. Using this method, we provide insights into how the spatial arrangement of the chromosome end structure is established and demonstrate that telomere folding is compromised throughout replicative senescence.

Download Full-text

rad21 Is Involved in Corneal Stroma Development by Regulating Neural Crest Migration

International Journal of Molecular Sciences ◽

10.3390/ijms21207807 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7807

Author(s):

Bi Ning Zhang ◽

Yu Liu ◽

Qichen Yang ◽

Pui Ying Leung ◽

Chengdong Wang ◽

...

Keyword(s):

Gene Expression ◽

Cell Migration ◽

Neural Crest ◽

Corneal Stroma ◽

Neural Crest Cell ◽

Chromosome Conformation ◽

Neural Crest Cell Migration ◽

Neural Crest Migration ◽

Crest Cell ◽

Xenopus Laevis Embryos

Previously, we identified RAD21R450C from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were performed using cells from family members affected by peripheral sclerocornea. Both gene expression and chromosome conformation of cell adhesion genes were affected in cells carrying the heterozygous rad21 variant. Since cell migration is essential in early embryonic development and sclerocornea is a congenital disease, we studied neural crest migration during cornea development in X. laevis embryos. In X. laevis embryos injected with rad21 mutant mRNA, neural crest migration was disrupted, and the number of neural crest-derived periocular mesenchymes decreased significantly in the corneal stroma region. Our data indicate that the RAD21R450C variant contributes to peripheral sclerocornea by modifying chromosome conformation and gene expression, therefore disturbing neural crest cell migration, which suggests RAD21 plays a key role in corneal stroma development.

Download Full-text