Dataset Information

Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.

ABSTRACT: The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study, we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction profiling by the chromosome conformation capture on chip (4C) technology with expression, protein occupancy, and chromatin accessibility profiles. This approach allowed a comprehensive analysis of how distinct features of the linear genome are organized in the three-dimensional nuclear space in the context of rapid gene regulation. We found that the transcriptional response to GR occurs without dramatic nuclear reorganization. Moreover, contrary to the view of transcription-driven organization, even genes with opposite transcriptional responses colocalize. Regions contacting GR-regulated genes are not particularly enriched for GR-regulated loci or for any functional group of genes, suggesting that these subnuclear environments are not organized to respond to a specific factor. The contact regions are, however, highly enriched for DNase I-hypersensitive sites that comprehensively mark cell-type-specific regulatory sites. These findings indicate that the nucleus is pre-organized in a conformation allowing rapid transcriptional reprogramming, and this organization is significantly correlated with cell-type-specific chromatin sites accessible to regulatory factors. Numerous open chromatin loci may be arranged in nuclear domains that are poised to respond to diverse signals in general and to permit efficient gene regulation.

SUBMITTER: Hakim O

PROVIDER: S-EPMC3083086 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.

Hakim Ofir O Sung Myong-Hee MH Voss Ty C TC Splinter Erik E John Sam S Sabo Peter J PJ Thurman Robert E RE Stamatoyannopoulos John A JA de Laat Wouter W Hager Gordon L GL

Genome research 20110406 5

The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study, we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction ...[more]

PMID: 21471403

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Project description:BackgroundThe data deluge can leverage sophisticated ML techniques for functionally annotating the regulatory non-coding genome. The challenge lies in selecting the appropriate classifier for the specific functional annotation problem, within the bounds of the hardware constraints and the model's complexity. In our system AIKYATAN, we annotate distal epigenomic regulatory sites, e.g., enhancers. Specifically, we develop a binary classifier that classifies genome sequences as distal regulatory regions or not, given their histone modifications' combinatorial signatures. This problem is challenging because the regulatory regions are distal to the genes, with diverse signatures across classes (e.g., enhancers and insulators) and even within each class (e.g., different enhancer sub-classes).ResultsWe develop a suite of ML models, under the banner AIKYATAN, including SVM models, random forest variants, and deep learning architectures, for distal regulatory element (DRE) detection. We demonstrate, with strong empirical evidence, deep learning approaches have a computational advantage. Plus, convolutional neural networks (CNN) provide the best-in-class accuracy, superior to the vanilla variant. With the human embryonic cell line H1, CNN achieves an accuracy of 97.9% and an order of magnitude lower runtime than the kernel SVM. Running on a GPU, the training time is sped up 21x and 30x (over CPU) for DNN and CNN, respectively. Finally, our CNN model enjoys superior prediction performance vis-'a-vis the competition. Specifically, AIKYATAN-CNN achieved 40% higher validation rate versus CSIANN and the same accuracy as RFECS.ConclusionsOur exhaustive experiments using an array of ML tools validate the need for a model that is not only expressive but can scale with increasing data volumes and diversity. In addition, a subset of these datasets have image-like properties and benefit from spatial pooling of features. Our AIKYATAN suite leverages diverse epigenomic datasets that can then be modeled using CNNs with optimized activation and pooling functions. The goal is to capture the salient features of the integrated epigenomic datasets for deciphering the distal (non-coding) regulatory elements, which have been found to be associated with functional variants. Our source code will be made publicly available at: https://bitbucket.org/cellsandmachines/aikyatan.

Project description:The Lim domain only 2 (Lmo2) gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Several distal regulatory elements have been identified upstream of the Lmo2 gene in the human and mouse genomes that are capable of enhancing reporter gene expression in erythroid cells and may be responsible for the high level transcription of Lmo2 in the erythroid lineage. In this study we investigate how these elements regulate transcription of Lmo2 and whether or not they function cooperatively in the endogenous context. Chromosome conformation capture (3C) experiments show that chromatin-chromatin interactions exist between upstream regulatory elements and the Lmo2 promoter in erythroid cells but that these interactions are absent from kidney where Lmo2 is transcribed at twelve fold lower levels. Specifically, long range chromatin-chromatin interactions occur between the Lmo2 proximal promoter and two broad regions, 3-31 and 66-105 kb upstream of Lmo2, which we term the proximal and distal control regions for Lmo2 (pCR and dCR respectively). Each of these regions is bound by several transcription factors suggesting that multiple regulatory elements cooperate in regulating high level transcription of Lmo2 in erythroid cells. Binding of CTCF and cohesin which support chromatin loops at other loci were also found within the dCR and at the Lmo2 proximal promoter. Intergenic transcription occurs throughout the dCR in erythroid cells but not in kidney suggesting a role for these intergenic transcripts in regulating Lmo2, similar to the broad domain of intergenic transcription observed at the human β-globin locus control region. Our data supports a model in which the dCR functions through a chromatin looping mechanism to contact and enhance Lmo2 transcription specifically in erythroid cells. Furthermore, these chromatin loops are supported by the cohesin complex recruited to both CTCF and transcription factor bound regions.

Dataset Information

Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.

Publications

Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.

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