scholarly journals 3D genome evolution and reorganization in the Drosophila melanogaster species group

2020 ◽  
Author(s):  
Nicole S. Torosin ◽  
Aparna Anand ◽  
Tirupathi Rao Golla ◽  
Weihuan Cao ◽  
Christopher E. Ellison
Keyword(s):  
Current Knowledge ◽  
Regulatory Element ◽  
Boundary Elements ◽  
Species Group ◽  
Evolutionary Divergence ◽  
Aberrant Expression ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Sequence Elements ◽  
Integral Role

AbstractTopologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts; there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the extent of TAD conservation across species is inconclusive. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ~15 million years ago. We find that 75% of TAD boundaries are orthologous while only 25% of TAD domains are conserved and these are enriched for Polycomb-repressed chromatin. Our results show that TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, yet the sequence elements that specify TAD boundaries remain highly conserved. We propose that evolutionary divergence in 3D genome organization results from shuffling of conserved boundary elements across chromosomes, breaking old TADs and creating new TAD architectures. This result supports the existence of distinct TAD subtypes: some may be evolutionarily flexible while others remain highly conserved due to their importance in restricting gene-regulatory element interactions.

scholarly journals 3D genome evolution and reorganization in the Drosophila melanogaster species group

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009229
Author(s):  
Nicole S. Torosin ◽  
Aparna Anand ◽  
Tirupathi Rao Golla ◽  
Weihuan Cao ◽  
Christopher E. Ellison
Keyword(s):  
Gene Expression ◽  
Evolutionary Dynamics ◽  
Current Knowledge ◽  
Regulatory Element ◽  
Chromosomal Rearrangements ◽  
Evolutionary Conservation ◽  
Species Group ◽  
Aberrant Expression ◽  
Chromosome Conformation ◽  
Evolutionary Forces

Topologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts and there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the patterns of TAD evolution across species is limited. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ∼15 million years ago. We find that the majority of TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, via a combination of chromosomal rearrangements and gain/loss of TAD boundaries. TAD reorganization between these two species is associated with a localized effect on gene expression, near the site of disruption. By separating TADs into subtypes based on their chromatin state, we find that different subtypes are evolving under different evolutionary forces. TADs enriched for broadly expressed, transcriptionally active genes are evolving rapidly, potentially due to positive selection, whereas TADs enriched for developmentally-regulated genes remain conserved, presumably due to their importance in restricting gene-regulatory element interactions. These results provide novel insight into the evolutionary dynamics of TADs and help to reconcile contradictory reports related to the evolutionary conservation of TADs and whether changes in TAD structure affect gene expression.

scholarly journals Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

2020 ◽  
Author(s):  
Konstantin Okonechnikov ◽  
Aylin Camgoz ◽  
Donglim Esther Park ◽  
Owen Chapman ◽  
Jens-Martin Hübner ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Chromosomal Rearrangements ◽  
Regulatory Elements ◽  
Genetic Alterations ◽  
Aberrant Expression ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Disease Subtype ◽  
Expression Of Genes ◽  
Novel Therapeutic

Abstract Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial RELA-fusion associated group and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment1. Although the molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF (insulators) and H3K27ac (active enhancers) ChIP-seq as well as gene expression and whole-genome DNA methylation profiling in primary and relapsed ependymoma tumors and cell lines to identify chromosomal rearrangements and regulatory mechanisms underlying aberrant expression of genes that are essential for ependymoma tumorigenesis. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) by intra- and inter-chromosomal structural variants, tumor-specific 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation as novel oncogenic mechanisms in ependymoma. Through inhibition experiments we validated that the newly identified genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived ependymoma models in a disease subtype-specific manner. Thus, this study identifies potential novel therapeutic vulnerabilities in ependymoma and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome conformations even in tumors that lack known genetic alterations.

scholarly journals HP1 drives de novo 3D genome reorganization in early Drosophila embryos

Nature ◽  
2021 ◽  
Author(s):  
Fides Zenk ◽  
Yinxiu Zhan ◽  
Pavel Kos ◽  
Eva Löser ◽  
Nazerke Atinbayeva ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Early Embryo ◽  
Heterochromatin Protein ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Genome Reorganization

AbstractFundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown1,2. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

3D genome structure reconstruction from chromosomal contact data

2017 ◽  
Author(s):  
◽  
Tuan Anh Trieu
Keyword(s):  
High Resolution ◽  
Genome Structure ◽  
Cell Types ◽  
3D Models ◽  
Graphic User Interface ◽  
Soft Constraints ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Manual Adjustment ◽  
The Relationship

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Different cell types of an organism have the same DNA sequence, but they can function differently because their difference in 3D organization allows them to express different genes and has different cellular functions. Understanding the 3D organization of the genome is the key to understand functions of the cell. Chromosome conformation capture techniques like Hi-C and TCC that can capture interactions between proximal chromosome fragments have allowed the study of 3D genome organization in high resolution and high through-put. My work focuses on developing computational methods to reconstruct 3D genome structures from Hi-C data. I presented three methods to reconstruct 3D genome and chromosome structures. The first method can build 3D genome models from soft constraints of contacts and non-contacts. This method utilizes the concept of contact and non-contact to reconstruct 3D models without translating interaction frequencies into physical distances. The translation is commonly used by other methods even though it makes a strong assumption about the relationship between interaction frequencies and physical distances. In synthetic dataset, when the relationship was known, my method performed comparably with other methods assuming the relationship. This shows the potential of my method for real Hi-C datasets where the relationship is unknown. The limitation of the method is that it has parameters requiring manual adjustment. I developed the second method to reconstruct 3D genome models. This method utilizes a commonly used function to translate interaction frequencies to physical distances to build 3D models. I proposed a novel way to derive soft constraints to handle inconsistency in the data and to make the method robust. Building 3D models at high resolution is a more challenging problem as the number of constraints is small and the feasible space is larger. I introduced a third method to build 3D chromosome models at high resolution. The method reconstructs models at low resolution and then uses them to guide the reconstruction of models at high resolution. The last part of my work is the development of a comprehensive tool with intuitive graphic user interface to analyze Hi-C data, reconstruct and analyze 3D models.

scholarly journals Chromatin interaction aware gene regulatory modeling with graph attention networks

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.

Species Delimitation and evolutionary history of tree frogs in the Hyla chinensis-group (Hylidae, Amphibian)

2019 ◽  
Author(s):  
Tao Pan ◽  
Guiyou Wu ◽  
Xing Kang ◽  
Peng Yan ◽  
Izaz Ali ◽  
...  
Keyword(s):  
Species Delimitation ◽  
Divergence Time ◽  
Distinct Species ◽  
Species Group ◽  
Early Miocene ◽  
Evolutionary Divergence ◽  
Dabie Mountains ◽  
Ancestral Area ◽  
Ancestral Area Reconstruction ◽  
History Of

Abstract Background Species are the cornerstone in many domains of biology research, which made the accurate species delimitation became critically important. In this study, the systematics and biogeography of the Hyla chinensis -group were analyzed based on phylogeny, species delimitation and ancestral area reconstruction methods.Results The phylogenetic results showed six specific clusters existed in the H. chinensis- group. BPP analysis indicated that six distinct species exist due to the high probability values (>0.95), which were also supported by the BF analysis. The divergence time of the H. chinensis -group is estimated to date back to 18.84 Mya in the early Miocene. Combining the results of ancestral area reconstruction, the H. chinensis -group might have originated from Guangxi-Hainan, then spread eastwardly and reached Nanling mountains, Wuyi mountains, Huangshan mountains and Taiwan. In rightabout colonization, it is gradually extended to the Yunnan-Guizhou Plateau, Sichuan basin, Qinling mountains and Dabie mountains. Considering the geological movement from early Miocene to Pliocene, the colonization pattern of the H. chinensis -group maybe closely related to the progressive uplift of Qinghai-Tibetan Plateau (QTP) and historical climate change.Conclusions Our study provides evidence for species delimitation and speciation process within the H. chinensis -group. Our study supports the hypothesis that the evolutionary divergence in this species group was a consequence of the progressive uplift of QTP and environmental change.

scholarly journals DNA Methylation Contributes to the Differential Expression Levels of Mecp2 in Male Mice Neurons and Astrocytes

2019 ◽  
Vol 20 (8) ◽  
pp. 1845 ◽  
Author(s):  
Vichithra R.B. Liyanage ◽  
Carl O. Olson ◽  
Robby M. Zachariah ◽  
James R. Davie ◽  
Mojgan Rastegar
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Autism Spectrum ◽  
Brain Cells ◽  
Specific Expression ◽  
Expression Levels ◽  
Mecp2 Duplication Syndrome ◽  
Cell Type Specific Expression

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons.

Two new species of Diodontus (Hymenoptera: Pemphredonidae) from the western Mediterranean and their phylogenetic relationships

2019 ◽  
Vol 151 (5) ◽  
pp. 558-583
Author(s):  
Eduardas Budrys ◽  
Anna Budrienė ◽  
Svetlana Orlovskytė ◽  
Villu Soon
Keyword(s):  
New Species ◽  
North Africa ◽  
Mitochondrial Gene ◽  
Species Group ◽  
Western Mediterranean ◽  
Evolutionary Divergence ◽  
Protein Coding ◽  
Variable Regions ◽  
Rdna Genes ◽  
Two New Species

AbstractTwo new species of Diodontus Curtis, 1834 (Hymenoptera: Pemphredonidae) are described. Diodontus polytylus Budrys new species is widespread in North Africa, from Libya and Chad to Morocco, as well as in southern Spain and Portugal. Diodontus guichardi Budrys new species was found in several localities in Morocco. The new species have small differences in their morphology; however, they can be easily separated using molecular characters. Comparison of 17 molecular markers has revealed that the highest evolutionary divergence is observed in mitochondrial gene ND6 and internal transcribed spacer ITS2. The variable regions of the nuclear rDNA genes 18S and 28S demonstrated the lowest evolutionary divergence; thus they were of the least use for species identification. The most coherent reconstruction of phylogeny, in comparison to other groups of markers, was obtained using exons of nuclear protein-coding genes. A provisional key to the species of D. minutus (Fabricius, 1793) species group of the Mediterranean Region is presented.

scholarly journals The DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 289 ◽  
Author(s):  
Ping Hong ◽  
Hao Jiang ◽  
Weize Xu ◽  
Da Lin ◽  
Qian Xu ◽  
...  
Keyword(s):  
Target Genes ◽  
High Efficiency ◽  
New Technology ◽  
Three Dimensional ◽  
Large Data ◽  
Regulatory Elements ◽  
Chromosome Conformation Capture ◽  
Genome Chromosome ◽  
Chromosome Conformation ◽  
3D Genome

It is becoming increasingly important to understand the mechanism of regulatory elements on target genes in long-range genomic distance. 3C (chromosome conformation capture) and its derived methods are now widely applied to investigate three-dimensional (3D) genome organizations and gene regulation. Digestion-ligation-only Hi-C (DLO Hi-C) is a new technology with high efficiency and cost-effectiveness for whole-genome chromosome conformation capture. Here, we introduce the DLO Hi-C tool, a flexible and versatile pipeline for processing DLO Hi-C data from raw sequencing reads to normalized contact maps and for providing quality controls for different steps. It includes more efficient iterative mapping and linker filtering. We applied the DLO Hi-C tool to different DLO Hi-C datasets and demonstrated its ability in processing large data with multithreading. The DLO Hi-C tool is suitable for processing DLO Hi-C and in situ DLO Hi-C datasets. It is convenient and efficient for DLO Hi-C data processing.

scholarly journals New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 164 ◽  
Author(s):  
Stefania Scala ◽  
Crescenzo D’Alterio ◽  
Samantha Milanesi ◽  
Alessandra Castagna ◽  
Roberta Carriero ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Cancer Biology ◽  
Current Knowledge ◽  
Chemotherapy Resistance ◽  
Response To Therapy ◽  
Aberrant Expression ◽  
Molecular Alterations ◽  
Whim Syndrome ◽  
C Terminus ◽  
Genomic Landscape

Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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