scholarly journals RNA Biogenesis Instructs Functional Inter-Chromosomal Genome Architecture

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandro Bertero
Keyword(s):  
Rna Polymerase Ii ◽  
Cardiac Myocyte ◽  
Three Dimensional ◽  
Mitotic Cell ◽  
Genome Architecture ◽  
3D Genome ◽  
Functional Relationships ◽  
Splicing Regulator ◽  
Rna Biogenesis ◽  
Chromatin Folding

Three-dimensional (3D) genome organization has emerged as an important layer of gene regulation in development and disease. The functional properties of chromatin folding within individual chromosomes (i.e., intra-chromosomal or in cis) have been studied extensively. On the other hand, interactions across different chromosomes (i.e., inter-chromosomal or in trans) have received less attention, being often regarded as background noise or technical artifacts. This viewpoint has been challenged by emerging evidence of functional relationships between specific trans chromatin interactions and epigenetic control, transcription, and splicing. Therefore, it is an intriguing possibility that the key processes involved in the biogenesis of RNAs may both shape and be in turn influenced by inter-chromosomal genome architecture. Here I present the rationale behind this hypothesis, and discuss a potential experimental framework aimed at its formal testing. I present a specific example in the cardiac myocyte, a well-studied post-mitotic cell whose development and response to stress are associated with marked rearrangements of chromatin topology both in cis and in trans. I argue that RNA polymerase II clusters (i.e., transcription factories) and foci of the cardiac-specific splicing regulator RBM20 (i.e., splicing factories) exemplify the existence of trans-interacting chromatin domains (TIDs) with important roles in cellular homeostasis. Overall, I propose that inter-molecular 3D proximity between co-regulated nucleic acids may be a pervasive functional mechanism in biology.

scholarly journals SARS-CoV-2 Restructures the Host Chromatin Architecture

2021 ◽  
Author(s):  
Ruoyu Wang ◽  
Joo-Hyung Lee ◽  
Feng Xiong ◽  
Jieun Kim ◽  
Lana Al Hasani ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Host Cells ◽  
Interferon Response ◽  
Genome Architecture ◽  
3D Genome ◽  
Chromatin Architecture ◽  
Severe Infections ◽  
Global Reduction ◽  
Host Chromatin

SARS-CoV-2 has made >190-million infections worldwide, thus it is pivotal to understand the viral impacts on host cells. Many viruses can significantly alter host chromatin, but such roles of SARS-CoV-2 are largely unknown. Here, we characterized the three-dimensional (3D) genome architecture and epigenome landscapes in human cells after SARS-CoV-2 infection, revealing remarkable restructuring of host chromatin architecture. High-resolution Hi-C 3.0 uncovered widespread A compartmental weakening and A-B mixing, together with a global reduction of intra-TAD chromatin contacts. The cohesin complex, a central organizer of the 3D genome, was significantly depleted from intra-TAD regions, supporting that SARS-CoV-2 disrupts cohesin loop extrusion. Calibrated ChIP-Seq verified chromatin restructuring by SARS-CoV-2 that is particularly manifested by a pervasive reduction of euchromatin modifications. Built on the rewired 3D genome/epigenome maps, a modified activity-by-contact model highlights the transcriptional weakening of antiviral interferon response genes or virus sensors (e.g., DDX58) incurred by SARS-CoV-2. In contrast, pro-inflammatory genes (e.g. IL-6) high in severe infections were uniquely regulated by augmented H3K4me3 at their promoters. These findings illustrate how SARS-CoV-2 rewires host chromatin architecture to confer immunological gene deregulation, laying a foundation to characterize the long-term epigenomic impacts of this virus.

scholarly journals Epigenomic and 3D genome architecture in naïve and primed human embryonic stem cell states

2017 ◽  
Author(s):  
Stephanie L. Battle ◽  
Naresh Doni Jayavelu ◽  
Robert N. Azad ◽  
Jennifer Hesson ◽  
Faria N. Ahmed ◽  
...  
Keyword(s):  
Human Embryonic Stem Cell ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Genome Architecture ◽  
Open Chromatin ◽  
Substantial Portion ◽  
3D Genome ◽  
Mammalian Embryogenesis ◽  
Post Implantation ◽  
Epigenomic Reprogramming

ABSTRACTDuring mammalian embryogenesis changes in morphology and gene expression are concurrent with epigenomic reprogramming. Using human embryonic stem cells representing the pre-implantation blastocyst (naïve) and post-implantation epiblast (primed), our data demonstrate that a substantial portion of known human enhancers are pre-marked by H3K4me1 in naïve cells, providing an enhanced open chromatin state in naïve pluripotency. The naïve enhancer repertoire occupies nine percent of the genome, three times that of primed cells, and can exist in broad chromatin domains over fifty kilobases. Enhancer chromatin states are largely poised. Seventy-seven percent of naïve enhancers are decommissioned in a stepwise manner as cells become primed. While primed topological associated domains are unaltered upon differentiation, naïve domains expand across primed boundaries, impacting three dimensional genome architecture. Differential topological associated domain edges coincide with naïve H3K4me1 enrichment. Our results suggest that naïve-derived cells have a chromatin landscape reflective of early embryogenesis.

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 Physical and data structure of 3D genome

2020 ◽  
Vol 6 (2) ◽  
pp. eaay4055 ◽  
Author(s):  
Kai Huang ◽  
Yue Li ◽  
Anne R. Shim ◽  
Ranya K. A. Virk ◽  
Vasundhara Agrawal ◽  
...  
Keyword(s):  
Double Helix ◽  
Three Dimensional ◽  
Polymer Physics ◽  
Point Of View ◽  
Linear Topology ◽  
3D Genome ◽  
Chromatin Folding ◽  
Tree Data ◽  
Dna Double Helix ◽  
Striking Contrast

With the textbook view of chromatin folding based on the 30-nm fiber being challenged, it has been proposed that interphase DNA has an irregular 10-nm nucleosome polymer structure whose folding philosophy is unknown. Nevertheless, experimental advances suggest that this irregular packing is associated with many nontrivial physical properties that are puzzling from a polymer physics point of view. Here, we show that the reconciliation of these exotic properties necessitates modularizing three-dimensional genome into tree data structures on top of, and in striking contrast to, the linear topology of DNA double helix. These functional modules need to be connected and isolated by an open backbone that results in porous and heterogeneous packing in a quasi–self-similar manner, as revealed by our electron and optical imaging. Our multiscale theoretical and experimental results suggest the existence of higher-order universal folding principles for a disordered chromatin fiber to avoid entanglement and fulfill its biological functions.

scholarly journals Deeply hidden genome organization directly mediated by SATB1

2021 ◽  
Author(s):  
Yoshinori Kohwi ◽  
Mari Grange ◽  
Hunter W Richards ◽  
Ya-Chen Liang ◽  
Cheng-Ming Chuong ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Genome Architecture ◽  
Cell Type ◽  
Topologically Associated Domains ◽  
Chromatin Folding ◽  
Cell Type Specific ◽  
Cellular Phenotypes

Mammalian genomes are organized by multi-layered chromatin folding. Whether and how three-dimensional genome organization contributes to cell-type specific transcription remains unclear. Here we uncover genome architecture formed by specialized sequences, base-unpairing regions (BURs), bound to a nuclear architectural protein, SATB1. SATB1 regulates cell-type specific transcription that underlies changes in cellular phenotypes. We developed a modified ChIP-seq protocol that stringently purifies genomic DNA only with its directly-associated proteins and unmasked previously-hidden BURs as direct SATB1 targets genome-wide. These SATB1-bound BURs are mutually exclusive from CTCF binding sites, and SATB1 is dispensable for CTCF/cohesion-mediated topologically associated domains (TADs). Instead, BURs largely overlap with lamina associated domains (LADs), and the fraction of BURs tethered to the SATB1 protein network in the nuclear interior is cell type-dependent. Our results reveal TAD-independent chromatin folding mediated by BUR sequences, which serve as genome architecture landmarks targeted by SATB1, to regulate cell-type specific gene expression.

3D genomics across the tree of life reveals condensin II as a determinant of architecture type

Science ◽  
2021 ◽  
Vol 372 (6545) ◽  
pp. 984-989
Author(s):  
Claire Hoencamp ◽  
Olga Dudchenko ◽  
Ahmed M. O. Elbatsh ◽  
Sumitabha Brahmachari ◽  
Jonne A. Raaijmakers ◽  
...  
Keyword(s):  
Human Genome ◽  
Physical Model ◽  
Common Ancestor ◽  
Three Dimensional ◽  
Tree Of Life ◽  
Genome Architecture ◽  
Last Common Ancestor ◽  
Eukaryotic Evolution ◽  
3D Genome ◽  
3D Genomics

We investigated genome folding across the eukaryotic tree of life. We find two types of three-dimensional (3D) genome architectures at the chromosome scale. Each type appears and disappears repeatedly during eukaryotic evolution. The type of genome architecture that an organism exhibits correlates with the absence of condensin II subunits. Moreover, condensin II depletion converts the architecture of the human genome to a state resembling that seen in organisms such as fungi or mosquitoes. In this state, centromeres cluster together at nucleoli, and heterochromatin domains merge. We propose a physical model in which lengthwise compaction of chromosomes by condensin II during mitosis determines chromosome-scale genome architecture, with effects that are retained during the subsequent interphase. This mechanism likely has been conserved since the last common ancestor of all eukaryotes.

scholarly journals MyoD is a structure organizer of 3D genome architecture in muscle cells

2020 ◽  
Author(s):  
Qian Chen ◽  
Fengling Chen ◽  
Ruiting Wang ◽  
Minglei Shi ◽  
Antony K. Chen ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Muscle Cells ◽  
Cell Types ◽  
Linear Molecule ◽  
Basic Question ◽  
Genome Architecture ◽  
Cell Type ◽  
3D Genome ◽  
A Genome

AbstractThe genome is not a linear molecule of DNA randomly folded in the nucleus, but exists as an organized, three-dimensional (3D) dynamic architecture. Intriguingly, it is now clear that each cell type has a unique and characteristic 3D genome organization that functions in determining cell identity during development. A currently challenging basic question is how cell-type specific 3D genome structures are established during development. Herein, we analyzed 3D genome structures in primary myoblasts and myocytes from MyoD knockout (MKO) and wild type (WT) mice and discovered that MyoD, a pioneer transcription factor (TF), can function as a “genome organizer” that specifies the proper 3D genome architecture unique to muscle cell development. Importantly, we genetically demonstrate that H3K27ac is insufficient for establishing MyoD-induced chromatin loops in muscle cells. The establishment of MyoD’s “architectural role” should have profound impacts on advancing understanding of other pioneer transcription factors in orchestrating lineage specific 3D genome organization during development in a potentially very large number of cell types in diverse organisms.

scholarly journals RNA polymerase II is required for spatial chromatin reorganization following exit from mitosis

2020 ◽  
Author(s):  
Shu Zhang ◽  
Nadine Übelmesser ◽  
Natasa Josipovic ◽  
Giada Forte ◽  
Johan A. Slotman ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Three Dimensional ◽  
Super Resolution ◽  
Mitotic Cell ◽  
Cycle Phase ◽  
Loop Formation ◽  
A Cell ◽  
Resolution Imaging ◽  
Chromatin Fractionation

SUMMARYMammalian chromosomes are three-dimensional entities shaped by converging and opposing forces. Mitotic cell division induces drastic chromosome condensation, but following reentry into the G1 cell cycle phase, condensed chromosomes unwind to reestablish interphase organization. Here, we use a cell line allowing auxin-mediated degradation of RNA polymerase II to test its role in this transition. In situ Hi-C showed that RNAPII is required for compartment and loop formation following mitosis. RNAPs often counteract loop extrusion and, in their absence, longer and more prominent loops arise. Evidence from chromatin fractionation, super-resolution imaging and in silico modeling attribute these effects to RNAPII-mediated cohesin loading at active promoters upon reentry into G1. Our findings reconcile the role of RNAPII in gene expression with that in chromatin architecture.

scholarly journals Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Roser Vilarrasa-Blasi ◽  
Paula Soler-Vila ◽  
Núria Verdaguer-Dot ◽  
Núria Russiñol ◽  
Marco Di Stefano ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Three Dimensional ◽  
Lymphocytic Leukemia ◽  
Genome Architecture ◽  
B Cell Differentiation ◽  
3D Genome ◽  
Chromatin Activation ◽  
Genome Interactions

AbstractTo investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a reversal to the naive state upon further maturation into memory B cells. B cell neoplasms are characterized by both entity and subtype-specific alterations in 3D genome organization, including large chromatin blocks spanning key disease-specific genes. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

scholarly journals Using DNase Hi-C techniques to map global and local three-dimensional genome architecture at high resolution

2017 ◽  
Author(s):  
Wenxiu Ma ◽  
Ferhat Ay ◽  
Choli Lee ◽  
Gunhan Gulsoy ◽  
Xinxian Deng ◽  
...  
Keyword(s):  
High Resolution ◽  
High Throughput ◽  
Three Dimensional ◽  
Dnase I ◽  
Genome Architecture ◽  
Whole Genome ◽  
Fine Scale ◽  
3D Genome ◽  
Dna Capture ◽  
Global And Local

AbstractThe folding and three-dimensional (3D) organization of chromatin in the nucleus critically impacts genome function. The past decade has witnessed rapid advances in genomic tools for delineating 3D genome architecture. Among them, chromosome conformation capture (3C)-based methods such as Hi-C are the most widely used techniques for mapping chromatin interactions. However, traditional Hi-C protocols rely on restriction enzymes (REs) to fragment chromatin and are therefore limited in resolution. We recently developed DNase Hi-C for mapping 3D genome organization, which uses DNase I for chromatin fragmentation. DNase Hi-C overcomes RE-related limitations associated with traditional Hi-C methods, leading to improved methodological resolution. Furthermore, combining this method with DNA capture technology provides a high-throughput approach (targeted DNase Hi-C) that allows for mapping fine-scale chromatin architecture at exceptionally high resolution. Hence, targeted DNase Hi-C will be valuable for delineating the physical landscapes of cis-regulatory networks that control gene expression and for characterizing phenotype-associated chromatin 3D signatures. Here, we provide a detailed description of method design and step-by-step working protocols for these two methods.HighlightsDNase Hi-C, a method for comprehensive mapping of chromatin contacts on a whole-genome scale, is based on random chromatin fragmentation by DNase I digestion instead of sequence-specific restriction enzyme (RE) digestion.Targeted DNase Hi-C, which combines DNase Hi-C with DNA capture technology, is a high-throughput method for mapping fine-scale chromatin architecture of genomic loci of interest at a resolution comparable to that of genomic annotations of functional elements.DNase Hi-C and targeted DNase Hi-C provide the first high-throughput way to overcome the RE-digestion-associated resolution limit of 3C-based methods.Step-by-step whole-genome and targeted DNase Hi-C protocols for mapping global and local 3D genome architecture, respectively, are described.

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