scholarly journals Understanding gene regulatory mechanisms based on gene classification

2021 ◽  
Author(s):  
Hao Tian ◽  
Yueying He ◽  
Yue Xue ◽  
Yi Qin Gao
Keyword(s):  
Gene Regulation ◽  
Density Distribution ◽  
Genome Organization ◽  
Housekeeping Genes ◽  
Structural Features ◽  
Regulatory Mechanisms ◽  
3D Genome ◽  
Human Genes ◽  
Cpg Dinucleotide ◽  
Gene Regulatory

The CpG dinucleotide and its methylation play vital roles in gene regulation as well as 3D genome organization. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites (TSS) and found that housekeeping genes tend to possess high CpG density while tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around TSS, the human genes are clearly divided into different categories. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, and correlation patterns between expression level and CpG/TpG density. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes, such as their CpG density distribution.

scholarly journals An information theoretic treatment of sequence-to-expression modeling

2018 ◽  
Author(s):  
Farzaneh Khajouei ◽  
Saurabh Sinha
Keyword(s):  
Gene Regulation ◽  
Transcription Factor ◽  
Probability Distribution ◽  
Experiment Design ◽  
Regulatory Mechanisms ◽  
Information Theoretic ◽  
Novel Approach ◽  
Reporter Assays ◽  
Gene Regulatory ◽  
Site Mutagenesis

AbstractStudying a gene’s regulatory mechanisms is a tedious process that involves identification of candidate regulators by transcription factor (TF) knockout or over-expression experiments, delineation of enhancers by reporter assays, and demonstration of direct TF influence by site mutagenesis, among other approaches. Such experiments are often chosen based on the biologist’s intuition, from several testable hypotheses. We pursue the goal of making this process systematic by using ideas from information theory to reason about experiments in gene regulation, in the hope of ultimately enabling rigorous experiment design strategies. For this, we make use of a state-of-the-art mathematical model of gene expression, which provides a way to formalize our current knowledge of cis- as well as trans-regulatory mechanisms of a gene. Ambiguities in such knowledge can be expressed as uncertainties in the model, which we capture formally by building an ensemble of plausible models that fit the existing data and defining a probability distribution over the ensemble. We then characterize the impact of a new experiment on our understanding of the gene’s regulation based on how the ensemble of plausible models and its probability distribution changes when challenged with results from that experiment. This allows us to assess the ‘value’ of the experiment retroactively as the reduction in entropy of the distribution (information gain) resulting from the experiment’s results. We fully formalize this novel approach to reasoning about gene regulation experiments and use it to evaluate a variety of perturbation experiments on two developmental genes of D. melanogaster. We also provide objective and ‘biologist-friendly’ descriptions of the information gained from each such experiment. The rigorously defined information theoretic approaches presented here can be used in the future to formulate systematic strategies for experiment design pertaining to studies of gene regulatory mechanisms.Author summaryIn-depth studies of gene regulatory mechanisms employ a variety of experimental approaches such as identifying a gene’s enhancer(s) and testing its variants through reporter assays, followed by transcription factor mis-expression or knockouts, site mutagenesis, etc. The biologist is often faced with the challenging problem of selecting the ideal next experiment to perform so that its results provide novel mechanistic insights, and has to rely on their intuition about what is currently known on the topic and which experiments may add to that knowledge. We seek to make this intuition-based process more systematic, by borrowing ideas from the mature statistical field of experiment design. Towards this goal, we use the language of mathematical models to formally describe what is known about a gene’s regulatory mechanisms, and how an experiment’s results enhance that knowledge. We use information theoretic ideas to assign a ‘value’ to an experiment as well as explain objectively what is learned from that experiment. We demonstrate use of this novel approach on two extensively studied developmental genes in fruitfly. We expect our work to lead to systematic strategies for selecting the most informative experiments in a study of gene regulation.

scholarly journals Predicted Archaic 3D Genome Organization Reveals Genes Related to Head and Spinal Cord Separating Modern from Archaic Humans

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 48 ◽  
Author(s):  
Daniel Batyrev ◽  
Elisheva Lapid ◽  
Liran Carmel ◽  
Eran Meshorer
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Genome Organization ◽  
Spinal Column ◽  
Detailed Comparison ◽  
Modern Human ◽  
High Coverage ◽  
3D Genome ◽  
Differentially Methylated Genes ◽  
Significant Enrichment

High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, archaic humans, and chimpanzees revealed 873 modern human-derived differentially methylated regions (DMRs). To understand the regulatory implications of these DMRs, we defined differentially methylated genes (DMGs) as genes that harbor DMRs in their promoter or gene body. While most of the modern human-derived DMRs could be linked to DMGs, many others remained unassigned. Here, we used information on 3D genome organization to link ~70 out of the remaining 288 unassigned DMRs to genes. Combined with the previously identified DMGs, we reinforce the enrichment of these genes with vocal and facial anatomy, and additionally find significant enrichment with the spinal column, chin, hair, and scalp. These results reveal the importance of 3D genomic organization in understanding gene regulation by DNA methylation.

scholarly journals Ranking of non-coding pathogenic variants and putative essential regions of the human genome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alex Wells ◽  
David Heckerman ◽  
Ali Torkamani ◽  
Li Yin ◽  
Jonathan Sebat ◽  
...  
Keyword(s):  
Genome Organization ◽  
Regulatory Elements ◽  
Structural Features ◽  
Loss Of Function ◽  
3D Genome ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Machine Learning Model ◽  
Using Data

AbstractA gene is considered essential if loss of function results in loss of viability, fitness or in disease. This concept is well established for coding genes; however, non-coding regions are thought less likely to be determinants of critical functions. Here we train a machine learning model using functional, mutational and structural features, including new genome essentiality metrics, 3D genome organization and enhancer reporter data to identify deleterious variants in non-coding regions. We assess the model for functional correlates by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements in over 3 Mb of genome sequence. Finally, we explore two user cases that involve indels and the disruption of enhancers associated with a developmental disease. We rank variants in the non-coding genome according to their predicted deleteriousness. The model prioritizes non-coding regions associated with regulation of important genes and with cell viability, an in vitro surrogate of essentiality.

scholarly journals Resolving the 3D landscape of transcription-linked mammalian chromatin folding

2019 ◽  
Author(s):  
Tsung-Han S. Hsieh ◽  
Elena Slobodyanyuk ◽  
Anders S. Hansen ◽  
Claudia Cattoglio ◽  
Oliver J. Rando ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Regulation ◽  
Genome Organization ◽  
Regulatory Elements ◽  
Genome Architecture ◽  
Transcriptional Regulatory Elements ◽  
3D Genome ◽  
Topologically Associating Domains ◽  
Transcriptional Regulatory ◽  
Chromatin Folding

ABSTRACTChromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into “microTADs” with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. Intriguingly, we detect “two-start” zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation.ONE SENTENCE SUMMARYTranscriptional regulatory elements shape 3D genome architecture of microTADs.

scholarly journals The origin of animals: an ancestral reconstruction of the unicellular-to-multicellular transition

Open Biology ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 200359
Author(s):  
Núria Ros-Rocher ◽  
Alberto Pérez-Posada ◽  
Michelle M. Leger ◽  
Iñaki Ruiz-Trillo
Keyword(s):  
Gene Regulation ◽  
Cell Communication ◽  
Regulatory Mechanisms ◽  
Comparative Genomic ◽  
Ancestral Reconstruction ◽  
Genomic Analyses ◽  
Gene Regulatory ◽  
Key Events ◽  
Early Developmental

How animals evolved from a single-celled ancestor, transitioning from a unicellular lifestyle to a coordinated multicellular entity, remains a fascinating question. Key events in this transition involved the emergence of processes related to cell adhesion, cell–cell communication and gene regulation. To understand how these capacities evolved, we need to reconstruct the features of both the last common multicellular ancestor of animals and the last unicellular ancestor of animals. In this review, we summarize recent advances in the characterization of these ancestors, inferred by comparative genomic analyses between the earliest branching animals and those radiating later, and between animals and their closest unicellular relatives. We also provide an updated hypothesis regarding the transition to animal multicellularity, which was likely gradual and involved the use of gene regulatory mechanisms in the emergence of early developmental and morphogenetic plans. Finally, we discuss some new avenues of research that will complement these studies in the coming years.

scholarly journals Environmental exposures and gene regulation in disease etiology

2008 ◽  
Vol 13 (1) ◽  
pp. 269-281 ◽  
Author(s):  
Thea M. Edwards ◽  
John Peterson Myers
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Environmental Exposures ◽  
Regulatory Mechanisms ◽  
Industrial Chemicals ◽  
Disease Etiology ◽  
Environmental Health Research ◽  
Genes And Environment ◽  
Broad Array ◽  
Gene Regulatory

Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. And the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.

scholarly journals 3DGV: Immersive Exploration of 3D Genome Structures using Virtual Reality

2019 ◽  
Author(s):  
Éric Zhang ◽  
Chrisostomos Drogaris ◽  
Antoine Gédon ◽  
Aaron Sossin ◽  
Rajae Faraj ◽  
...  
Keyword(s):  
Virtual Reality ◽  
Genome Organization ◽  
Spatial Organization ◽  
Genomic Data ◽  
Regulatory Mechanisms ◽  
3D Genome ◽  
Open Platform ◽  
3D Objects ◽  
Link Type ◽  
Genome Viewer

The analysis of 3D genomic data is expected to revolutionize our understanding of genome organization and regulatory mechanisms. Yet, the complex spatial organization of this information can be difficult to interpret with 2D viewers. Virtual Reality (VR) technologies offer an opportunity to rethink our methods to visualize and navigate 3D objects. In this paper, we introduce the Virtual Reality 3D Genome Viewer (3DGV), an open platform to experiment and develop VR solutions to explore 3D genome structures.Availabilityhttp://3dgv.cs.mcgill.ca/

scholarly journals The 3D genome organization of Drosophila melanogaster through data integration

2017 ◽  
Author(s):  
Qingjiao Li ◽  
Harianto Tjong ◽  
Xiao Li ◽  
Ke Gong ◽  
Xianghong Jasmine Zhou ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Data Integration ◽  
Genome Organization ◽  
Genome Structure ◽  
Structural Features ◽  
Embryonic Cells ◽  
Data Types ◽  
Chromosome Conformation ◽  
Topological Domains ◽  
3D Genome

AbstractGenome structures are dynamic and non-randomly organized in the nucleus of higher eukaryotes. To maximize the accuracy and coverage of 3D genome structural models, it is important to integrate all available sources of experimental information about a genome’s organization. It remains a major challenge to integrate such data from various complementary experimental methods. Here, we present an approach for data integration to determine a population of complete 3D genome structures that are statistically consistent with data from both genome-wide chromosome conformation capture (Hi-C) and lamina-DamID experiments. Our structures resolve the genome at the resolution of topological domains, and reproduce simultaneously both sets of experimental data. Importantly, this framework allows for structural heterogeneity between cells, and hence accounts for the expected plasticity of genome structures. As a case study we choose Drosophila melanogaster embryonic cells, for which both data types are available. Our 3D geome structures have strong predictive power for structural features not directly visible in the initial data sets, and reproduce experimental hallmarks of the D. melanogaster genome organization from independent and our own imaging experiments. Also they reveal a number of new insights about the genome organization and its functional relevance, including the preferred locations of heterochromatic satellites of differnet chromosomes, and observations about homologous pairing that cannot be directly observed in the original Hi-C or lamina-DamID data. To our knowledge our approach is the first that allows systematic integration of Hi-C and lamina DamID data for complete 3D genome structure calculation, while also explicitly considering genome structural variability.

scholarly journals Toward an understanding of the relation between gene regulation and 3D genome organization

2020 ◽  
Vol 8 (4) ◽  
pp. 295-311
Author(s):  
Hao Tian ◽  
Ying Yang ◽  
Sirui Liu ◽  
Hui Quan ◽  
Yi Qin Gao
Keyword(s):  
Gene Regulation ◽  
Genome Organization ◽  
3D Genome

scholarly journals Toward an understanding of the relation between gene regulation and 3D genome organization

2020 ◽  
Author(s):  
Hao Tian ◽  
Ying Yang ◽  
Sirui Liu ◽  
Hui Quan ◽  
Yi Qin Gao
Keyword(s):  
Gene Regulation ◽  
Chromatin Structure ◽  
Genome Organization ◽  
Network Formation ◽  
Expression Profiles ◽  
Chromosome Conformation ◽  
Tissue Specific ◽  
3D Genome ◽  
Gene Positioning ◽  
3D Chromatin Structure

AbstractThe development and usage of chromosome conformation capture technologies have provided great details on 3D genome organization and provide great opportunities to understand how gene regulation is affected by the 3D chromatin structure. Previously, we identified two types of sequence domains, CGI forest and CGI prairie, which tend to segregate spatially, but to different extent in different tissues/cell states. To further quantify the association of domain segregation with gene regulation and differentiation, we analyzed in this study the distribution of genes of different tissue specificities along the linear genome, and found that the distribution patterns are distinctly different in forests and prairies. The tissue-specific genes (TSGs) are significantly enriched in the latter but not in the former and genes of similar expression profiles among different cell types (co-activation/repression) also tend to cluster in specific prairies. We then analyzed the correlation between gene expression and the spatial contact revealed in Hi-C measurement. Tissue-specific forest-prairie contact formation was found to correlate with the regulation of the TSGs, in particular those in the prairie domains, pointing to the important role gene positioning, in the linear DNA sequence as well as in 3D chromatin structure, plays in gene regulatory network formation.

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