Spatial positioning is a fundamental principle governing nuclear processes. Chromatin is organized as a hierarchy from nucleosomes to Mbp chromatin domains (CD) or topologically associating domains (TADs) to higher level compartments culminating in chromosome territories (CT). Microscopic and sequencing techniques have substantiated chromatin organization as a critical factor regulating gene expression. For example, enhancers loop back to interact with their target genes almost exclusively within TADs, distally located coregulated genes reposition into common transcription factories upon activation, and Mbp CDs exhibit dynamic motion and configurational changes in vivo. A longstanding question in the nucleus field is whether an interactive nuclear matrix provides a direct link between structure and function. The findings of nonrandom radial positioning of CT within the nucleus suggest the possibility of preferential interaction patterns among populations of CT. Sequential labeling up to 10 CT followed by application of computer imaging and geometric graph mining algorithms revealed cell‐type specific interchromosomal networks (ICN) of CT that are altered during the cell cycle, differentiation, and cancer progression. It is proposed that the ICN correlate with the global level of genome regulation. These approaches also demonstrated that the large scale 3‐D topology of CT is specific for each CT. The cell‐type specific proximity of certain chromosomal regions in normal cells may explain the propensity of distinct translocations in cancer subtypes. Understanding how genes are dysregulated upon disruption of the normal “wiring” of the nucleus by translocations, deletions, and amplifications that are hallmarks of cancer, should enable more targeted therapeutic strategies.
- NSF-PAR ID:
- 10280072
- Date Published:
- Journal Name:
- International Journal of Molecular Sciences
- Volume:
- 22
- Issue:
- 1
- ISSN:
- 1422-0067
- Page Range / eLocation ID:
- 347
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
more » « less
Abstract Mammalian genomes are folded into a hierarchy of compartments, topologically associating domains (TADs), subTADs, and long-range looping interactions. The higher-order folding patterns of chromatin contacts within TADs and how they localize to disease-associated single nucleotide variants (daSNVs) remains an open area of investigation. Here, we analyze high-resolution Hi-C data with graph theory to understand possible mesoscale network architecture within chromatin domains. We identify a subset of TADs exhibiting strong core-periphery mesoscale structure in embryonic stem cells, neural progenitor cells, and cortical neurons. Hyper-connected core nodes co-localize with genomic segments engaged in multiple looping interactions and enriched for occupancy of the architectural protein CCCTC binding protein (CTCF). CTCF knockdown and
in silico deletion of CTCF-bound core nodes disrupts core-periphery structure, whereasin silico mutation of cell type-specific enhancer or gene nodes has a negligible effect. Importantly, neuropsychiatric daSNVs are significantly more likely to localize with TADs folded into core-periphery networks compared to domains devoid of such structure. Together, our results reveal that a subset of TADs encompasses looping interactions connected into a core-periphery mesoscale network. We hypothesize that daSNVs in the periphery of genome folding networks might preserve global nuclear architecture but cause local topological and functional disruptions contributing to human disease. By contrast, daSNVs co-localized with hyper-connected core nodes might cause severe topological and functional disruptions. Overall, these findings shed new light into the mesoscale network structure of fine scale genome folding within chromatin domains and its link to common genetic variants in human disease. -
During transition of human Neural Progenitor Cells (NPC) to Neuronal Committed Cells (NCC) activities of 4706 genes change their activities. These changes obey the Gaussian principle whereby the majority are moderate and few represent extreme up- or down-regulations. Inhibition of pan-ontogenic nuclear Fibroblast Growth Factor Receptor 1 (nFGFR1) signaling, which mediates the NPC to NCC differentiation, affected the activities of hundreds of genes in NPC and in NCC. Our new results show that nFGFR1 acts as a Band-Path filter that maintains global genome function within a homeostatic range by diminishing extreme changes and promoting moderate changes. To elaborate on the underlying mechanism, we analyzed Pearson correlation among the genes of the regulated genome. The majority of 4007 gene activities were highly coordinated and their frequencies were increased during the NPC to NCC transition while the low coordinated genes were decreased. The frequencies of high and low coordinated genes were affected by the inhibition of endogenous nFGFR1 and by the overexpression of constitutively active nFGFR1. Analysis of Gene Activity Networks (GANs) formed by the most coordinated neurodevelopmental genes showed that NPC to NCC transition is accompanied by a deconstruction of NPC GANs and construction of new NCC GANs and that the formation of GANs is largely dependent on the endogenous levels of nFGFR1. Within the GANs we identified several overrepresented Recurring Correlation Motifs (RCM) which undergo frequency redistribution during differentiation. The high complexity motifs (with a high number of connections) increased during GANs’ construction and decreased during GANs’ deconstruction. The ability of the RCM to counteract excessive gene activity oscillation during differentiation was analyzed by modelling their function as electrical RLC equivalent networks with genes serving as inductors (L) and the equivalent Spring-mass oscillator model. In RLC circuits, where the reduced inductance value from star network arrangement dampens the oscillations, increased motifs complexity dampens down the oscillations in the individual nodes (genes) activities as the network transits between different activity levels. In conclusion, deselection of low complexity of motifs and selection of more complex motifs by nFGFR1 serve to maintain the genome homeostasis during development. A Proportional–Integral–Derivative (PID) controller model with the RLC lumped element equivalents is proposed employing nFGFR1 feedback as a control system of the ontogenic gene programs.more » « less
-
more » « less
Abstract Distal regulatory elements influence the activity of gene promoters through chromatin looping. Chromosome conformation capture (3C) methods permit identification of chromatin contacts across different regions of the genome. However, due to limitations in the resolution of these methods, the detection of functional chromatin interactions remains a challenge. In the current study, we employ an integrated approach to define and characterize the functional chromatin contacts of human pancreatic cancer cells. We applied tethered chromatin capture to define classes of chromatin domains on a genome‐wide scale. We identified three types of structural domains (topologically associated, boundary, and gap) and investigated the functional relationships of these domains with respect to chromatin state and gene expression. We uncovered six distinct sub‐domains associated with epigenetic states. Interestingly, specific epigenetically active domains are sensitive to treatment with histone acetyltransferase (HAT) inhibitors and decrease in H3K27 acetylation levels. To examine whether the subdomains that change upon drug treatment are functionally linked to transcription factor regulation, we compared TCF7L2 chromatin binding and gene regulation to HAT inhibition. We identified a subset of coding RNA genes that together can stratify pancreatic cancer patients into distinct survival groups. Overall, this study describes a process to evaluate the functional features of chromosome architecture and reveals the impact of epigenetic inhibitors on chromosome architecture and identifies genes that may provide insight into disease outcome.
-
Abstract The organization of chromatin into self-interacting domains is universal among eukaryotic genomes, though how and why they form varies considerably. Here we report a chromosome-scale reference genome assembly of pepper ( Capsicum annuum ) and explore its 3D organization through integrating high-resolution Hi-C maps with epigenomic, transcriptomic, and genetic variation data. Chromatin folding domains in pepper are as prominent as TADs in mammals but exhibit unique characteristics. They tend to coincide with heterochromatic regions enriched with retrotransposons and are frequently embedded in loops, which may correlate with transcription factories. Their boundaries are hotspots for chromosome rearrangements but are otherwise depleted for genetic variation. While chromatin conformation broadly affects transcription variance, it does not predict differential gene expression between tissues. Our results suggest that pepper genome organization is explained by a model of heterochromatin-driven folding promoted by transcription factories and that such spatial architecture is under structural and functional constraints.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/ijms22010347
