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Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

ABSTRACT: A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.

SUBMITTER: Kieffer-Kwon KR

PROVIDER: S-EPMC3905448 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

Kieffer-Kwon Kyong-Rim KR Tang Zhonghui Z Mathe Ewy E Qian Jason J Sung Myong-Hee MH Li Guoliang G Resch Wolfgang W Baek Songjoon S Pruett Nathanael N Grøntved Lars L Vian Laura L Nelson Steevenson S Zare Hossein H Hakim Ofir O Reyon Deepak D Yamane Arito A Nakahashi Hirotaka H Kovalchuk Alexander L AL Zou Jizhong J Joung J Keith JK Sartorelli Vittorio V Wei Chia-Lin CL Ruan Xiaoan X Hager Gordon L GL Ruan Yijun Y Casellas Rafael R

Cell 20131201 7

A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find tha ...[more]

PMID: 24360274

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Project description:The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point-the intermediate metabolite alpha-isopropylmalate (alphaIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when alphaIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture.

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Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

Publications

Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

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