Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells
TL;DR: The first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues reveals extensive and preferential intra- and interchromosomal transcription interactomes, establishing a new gene expression paradigm.
Abstract: Peter Fraser and colleagues report a genome-wide analysis of transcription interactions involving the globin genes in mouse erythroid cells. They demonstrate that the transcription factor Klf1 mediates preferential co-associations between genes it regulates.
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TL;DR: The Genomic Regions Enrichment of Annotations Tool (GREAT) is developed to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome.
Abstract: We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.
3,730 citations
TL;DR: A high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei is presented, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.
1,817 citations
Cites background from "Preferential associations between c..."
...These networks involve transcriptionally active genes (Apostolou and Thanos, 2008; Hu et al., 2008; Noordermeer et al., 2011; Schoenfelder et al., 2010; Simonis et al., 2006), imprinted genes (Zhao et al., 2006), or genes repressed by Polycomb group (PcG) proteins (Bantignies et al., 2011; Tolhuis…...
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...These networks involve transcriptionally active genes (Apostolou and Thanos, 2008; Hu et al., 2008; Noordermeer et al., 2011; Schoenfelder et al., 2010; Simonis et al., 2006), imprinted genes (Zhao et al....
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TL;DR: Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns.
Abstract: Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns
1,367 citations
TL;DR: In conclusion, this study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells through widespread promoter-centered intragenic, extragenics, and intergenic interactions.
1,166 citations
Cites background from "Preferential associations between c..."
...…only 1,328 multigene complexes in this combined pilot dataset, 11,723 genes were engaged in these complexes for an average of 8.8 genes per interaction complex (Figure 1D), indicating that promoter-promoter interactions were widespread and may play a significant role in transcription regulation....
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...Gene Ontology (GO) analysis revealed significant enrichment of erythroid related GO terms such as response to stimulus and blood circulation for genes with specific expression and chromatin interactions in K562 cells, whereas GO terms such as ectoderm development and related biological process were…...
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...…Support Synergistic Transcription Regulation To further investigate the likelihood that the multigene complex structure might provide a topological framework for transcriptional coregulation of interacting genes involved in such topology, we designed a set of perturbation experiments to test this....
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TL;DR: A selection of recent studies that have probed histone modifications and successive layers of chromatin structure in mammalian genomes, the patterns that have been identified and future directions for research are reviewed.
Abstract: A succession of technological advances over the past decade have enabled researchers to chart maps of histone modifications and related chromatin structures with increasing accuracy, comprehensiveness and throughput. The resulting data sets highlight the interplay between chromatin and genome function, dynamic variations in chromatin structure across cellular conditions, and emerging roles for large-scale domains and higher-ordered chromatin organization. Here we review a selection of recent studies that have probed histone modifications and successive layers of chromatin structure in mammalian genomes, the patterns that have been identified and future directions for research.
1,112 citations
Cites background from "Preferential associations between c..."
...Together with ongoing studies of additional structures, such as transcription factories and nucleolus-associated domain...
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References
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TL;DR: Using the yeast Saccharomyces cerevisiae, this work could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis and found that chromatin is highly flexible throughout.
Abstract: We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.
3,465 citations
TL;DR: The results demonstrate that gene expression in mammalian cells is subject to large, intrinsically random fluctuations and raise questions about how cells are able to function in the face of such noise.
Abstract: Individual cells in genetically homogeneous populations have been found to express different numbers of molecules of specific proteins. We investigated the origins of these variations in mammalian cells by counting individual molecules of mRNA produced from a reporter gene that was stably integrated into the cell's genome. We found that there are massive variations in the number of mRNA molecules present in each cell. These variations occur because mRNAs are synthesized in short but intense bursts of transcription beginning when the gene transitions from an inactive to an active state and ending when they transition back to the inactive state. We show that these transitions are intrinsically random and not due to global, extrinsic factors such as the levels of transcriptional activators. Moreover, the gene activation causes burst-like expression of all genes within a wider genomic locus. We further found that bursts are also exhibited in the synthesis of natural genes. The bursts of mRNA expression can be buffered at the protein level by slow protein degradation rates. A stochastic model of gene activation and inactivation was developed to explain the statistical properties of the bursts. The model showed that increasing the level of transcription factors increases the average size of the bursts rather than their frequency. These results demonstrate that gene expression in mammalian cells is subject to large, intrinsically random fluctuations and raise questions about how cells are able to function in the face of such noise.
1,728 citations
TL;DR: JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes that were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors.
Abstract: The analysis of regulatory regions in genome sequences is strongly based on the detection of potential transcription factor binding sites. The preferred models for representation of transcription factor binding specificity have been termed position-specific scoring matrices. JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions. JASPAR is available at http://jaspar. cgb.ki.se.
1,704 citations
TL;DR: It is demonstrated here that active and inactive genes are engaged in many long-range intrachromosomal interactions and can also form interchromosomal contacts and establish 4C technology as a powerful tool to study nuclear architecture.
Abstract: The spatial organization of DNA in the cell nucleus is an emerging key contributor to genomic function1,2,3,4,5,6,7,8,9,10,11,12. We developed 4C technology (chromosome conformation capture (3C)-on-chip), which allows for an unbiased genome-wide search for DNA loci that contact a given locus in the nuclear space. We demonstrate here that active and inactive genes are engaged in many long-range intrachromosomal interactions and can also form interchromosomal contacts. The active β-globin locus in fetal liver preferentially contacts transcribed, but not necessarily tissue-specific, loci elsewhere on chromosome 7, whereas the inactive locus in fetal brain contacts different transcriptionally silent loci. A housekeeping gene in a gene-dense region on chromosome 8 forms long-range contacts predominantly with other active gene clusters, both in cis and in trans, and many of these intra- and interchromosomal interactions are conserved between the tissues analyzed. Our data demonstrate that chromosomes fold into areas of active chromatin and areas of inactive chromatin and establish 4C technology as a powerful tool to study nuclear architecture.
1,354 citations
TL;DR: A robust approach is described that couples chromatin immunoprecipitation (ChIP) with the paired-end ditag (PET) sequencing strategy for unbiased and precise global localization of transcription-factor binding sites (TFBS).
1,180 citations