Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

Neems, Daniel; Garza-Gongora, Arturo G.; Smith, Erica D.; Kosak, Steven T.

doi:10.1073/pnas.1521826113

Cited by 43 publications

(37 citation statements)

References 61 publications

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“…5; Additional file 14). TADs flanking gene arrays experiencing transcriptional upregulation during differentiation show enrichment for histone marks peculiar for open chromatin and were devoid of histone marks peculiar for compact chromatin (Additional file 3: Figure S12) consistent with previous observations [53, 69]. Overall, the muscle-specific genes showed high levels of clustering with genomic regions that were modified by the epigenetic features that were tested before and after differentiation into myotubes (Fig.…”

Section: Resultssupporting

confidence: 88%

“…This is consistent with the known tight coupling between cell proliferation and differentiation [86–88]. Interestingly, it has been recently shown that cell division is a necessary prerequisite for establishing changes in nuclear architecture during myogenesis in human cells [69]. Furthermore, the concomitant expression of these two groups of genes is generally reciprocal [10, 11], and the ‘crosstalk’ in terms of interactions may contribute to such reciprocity.…”

Section: Discussionsupporting

confidence: 77%

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Linkages between changes in the 3D organization of the genome and transcription during myotube differentiation in vitro

et al. 2017

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BackgroundThe spatial organization of eukaryotic genomes facilitates and reflects the underlying nuclear processes that are occurring in the cell. As such, the spatial organization of a genome represents a window on the genome biology that enables analysis of the nuclear regulatory processes that contribute to mammalian development.MethodsIn this study, Hi-C and RNA-seq were used to capture the genome organization and transcriptome in mouse muscle progenitor cells (C2C12 myoblasts) before and after differentiation to myotubes, in the presence or absence of the cytidine analogue AraC.ResultsWe observed significant local and global developmental changes despite high levels of correlation between the myotubes and myoblast genomes. Notably, the genes that exhibited the greatest variation in transcript levels between the different developmental stages were predominately within the euchromatic compartment. There was significant re-structuring and changes in the expression of replication-dependent histone variants within the HIST1 locus. Finally, treating terminally differentiated myotubes with AraC resulted in additional changes to the transcriptome and 3D genome organization of sets of genes that were all involved in pyroptosis.ConclusionsCollectively, our results provide evidence for muscle cell-specific responses to developmental and environmental stimuli mediated through a chromatin structure mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-017-0122-1) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 77%

Linkages between changes in the 3D organization of the genome and transcription during myotube differentiation in vitro

et al. 2017

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“…Although why this may occur has yet to be fully explained, we have evidence suggesting that homologous gene loci that are spatially proximal in the nuclear compartment tend to have similar expression levels, i.e. reduced transcriptional noise [29]. It is possible that loci residing in large chromatin domains on chromosome homologs could potentially behave similarly.…”

Section: Discussionmentioning

confidence: 96%

“…TADs are flanked by CTCF-binding sequences that appear to constrain the interactivity of the chromatin confined within a given region [26,27]. The size and distribution of TADs appear to be cell-type invariant; however, the genes contained within each distinct TAD boundary have been found to be coordinately regulated and may inform the 3D nuclear localization of TADs [28,29]. Although 3C based techniques have been successful in providing genome wide resolution of cis-interacting chromatin, they have yet to fully characterize interchromosomal associations, as these interactions are hard to detect by these strategies.…”

Section: Introductionmentioning

confidence: 99%

Modeling gene expression networks to predict interchromosomal organization during human embryonic stem cell differentiation

Laster¹,

Garza-Gongora²,

Daley³

et al. 2018

Preprint

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Cellular differentiation occurs through the regulation of lineage-specific gene expression networks that are facilitated by the spatial organization of the genome. Although techniques based on the chromatin conformation capture (3C) approach have yielded intrachromosomal genome-wide interaction maps, strategies to identify non-random interchromosomal associations is lacking. Therefore, we modeled the genomic organization of chromosomes based on the regulatory networks involved in the differentiation of pluripotent human embryonic stem cells (hESCs) to committed neuronal precursor cells (cNPCs). Importantly, transcriptional regulation has been demonstrated to be a driving force in nonrandom genome organization. Thus, we constructed coarse-grained in silico networks using gene expression data to identify potential physical associations among chromosomes occurring in situ and then analyzed the three-dimensional (3D) distribution of these chromosomes, assessing how their associations contribute to nuclear organization. Our analysis suggests that coordinate regulation of differentially expressed genes is correlated with the 3D organization of chromosomes in hESC nuclei induced to differentiate to cNPCs. Author SummaryThe cellular commitment and differentiation of stem cells is a hallmark of metazoan development. The ultimate fate of a stem cell is defined by the synergistic modulation of key gene regulatory networks within the nucleus. In our work, we formulate an in silico model describing how the similarity in the expression profile of differentially regulated gene networks is correlated with the higher-order organization of chromosomes during differentiation from human embryonic stem cells (hESCs) to committed neuronal precursor cells (cNPCs). Using graph statistics, we observe that the genome networks generated using the in silico model exhibit properties similar to real-world networks. In addition to modeling how gene expression relates to dynamic changes in chromosome organization, we test the model by calculating the relative proximity of multiple chromosome pairs using 3D fluorescence in situ hybridization (FISH). While various chromosomal properties, including gene density and overall length, have been attributed to chromosome organization, our previous work has identified the emergence of cell-type specific chromosomal topologies related to coordinate gene regulation during cellular differentiation. Here we extend these findings by determining whether our in silico model can predict chromosome association based upon coordinate gene expression. Our work supports the idea that gene co-regulation, in addition to inherent organizational constraints of the nucleus, influences three-dimensional chromosome organization.

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“…Systematic depletion of CTCF and Cohesins also leads to de-insulation and partial disruption of TADs 20,21 . An array of studies has shown that TADs function as basic units of 3D genome that dynamically associate with the epigenetic states of genes, including replication timing, during development and differentiation [22][23][24][25][26][27][28][29][30] . How these dynamical epigenetic states of TADs are regulated is not entirely clear.…”

Section: Introductionmentioning

confidence: 99%

Biased visibility in HiC datasets marks dynamically regulated condensed and decondensed chromatin states genome-wide

Chandradoss

Guthikonda

Kethavath

et al. 2018

Preprint

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Proximity ligation based techniques, like HiC, involve restriction digestion followed by ligation of formaldehyde cross-linked chromatin. We showed that the HiC datasets have significant bias due to differential accessibility of chromatin domains to restriction endonucleases. Through analysis of lamina-associated domains (LADs), inactive X-chromosome in mammals and polytene bands in fly, we established that the DNA in condensed chromatin had lesser accessibility to nucleases used in HiC as compared to that in decondensed chromatin. The observed bias was independent of known systematic biases attributed to length and GC content of the restriction fragments and was not appropriately corrected by computational methods. We identified novel condensed domains outside LADs, which were bordered by insulators and were dynamically associated with the developmentally regulated epigenetic and transcriptional states. Our observations suggested that the corrected read counts of existing HiC datasets can be reliably repurposed to study the dynamics of chromatin condensation and decondensation and that the existing HiC datasets should be interpreted with cautions.

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Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

Cited by 43 publications

References 61 publications

Linkages between changes in the 3D organization of the genome and transcription during myotube differentiation in vitro

Linkages between changes in the 3D organization of the genome and transcription during myotube differentiation in vitro

Modeling gene expression networks to predict interchromosomal organization during human embryonic stem cell differentiation

Biased visibility in HiC datasets marks dynamically regulated condensed and decondensed chromatin states genome-wide

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