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

Kyong Rim Kieffer-Kwon; Zhonghui Tang; Ewy Mathe; Jason Qian; Myong Hee Sung; Guoliang Li; Wolfgang Resch; Songjoon Baek; Nathanael Pruett; Lars Grøntved; Laura Vian; Steevenson Nelson; Hossein Zare; Ofir Hakim; Deepak Reyon; Arito Yamane; Hirotaka Nakahashi; Alexander L. Kovalchuk; Jizhong Zou; J. Keith Joung; Vittorio Sartorelli; Chia Lin Wei; Xiaoan Ruan; Gordon L. Hager; Yijun Ruan; Rafael Casellas

doi:10.1016/j.cell.2013.11.039

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

Kyong Rim Kieffer-Kwon, Zhonghui Tang, Ewy Mathe, Jason Qian, Myong Hee Sung, Guoliang Li, Wolfgang Resch, Songjoon Baek, Nathanael Pruett, Lars Grøntved, Laura Vian, Steevenson Nelson, Hossein Zare, Ofir Hakim, Deepak Reyon, Arito Yamane, Hirotaka Nakahashi, Alexander L. Kovalchuk, Jizhong Zou, J. Keith JoungVittorio Sartorelli, Chia Lin Wei, Xiaoan Ruan, Gordon L. Hager, Yijun Ruan, Rafael Casellas

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

265 Scopus citations

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.

Original language	English
Pages (from-to)	1507-1520
Number of pages	14
Journal	Cell
Volume	155
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2013.11.039
State	Published - 19 Dec 2013

Bibliographical note

Funding Information:
We thank Kefei Yu for CH12 cells and protocols; J. Simone and J. Lay for cell sorting; G. Gutierrez for technical assistance with Illumina analyzer. This work was supported by the Intramural Research Program of NIAMS and NCI, and internal Jackson Laboratory fund JAX19020120 to Y.R. J.K.J. was supported by NIH grants DP1 GM105378 and P50 HG005550, the Defense Advanced Research Projects Agency grant W911NF-11-2-0056 and The Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.Q. was supported by the NIH UGSP program. All animal experiments were performed according to NIH guidelines. High-performance computation was performed using NIH Helix Systems ( http://helix.nih.gov ). J.K.J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Funding

We thank Kefei Yu for CH12 cells and protocols; J. Simone and J. Lay for cell sorting; G. Gutierrez for technical assistance with Illumina analyzer. This work was supported by the Intramural Research Program of NIAMS and NCI, and internal Jackson Laboratory fund JAX19020120 to Y.R. J.K.J. was supported by NIH grants DP1 GM105378 and P50 HG005550, the Defense Advanced Research Projects Agency grant W911NF-11-2-0056 and The Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.Q. was supported by the NIH UGSP program. All animal experiments were performed according to NIH guidelines. High-performance computation was performed using NIH Helix Systems ( http://helix.nih.gov ). J.K.J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Funders	Funder number
Ann Orr Massachusetts General Hospital
National Institutes of Health	P50 HG005550, DP1 GM105378
National Cancer Institute	JAX19020120
National Institute of Arthritis and Musculoskeletal and Skin Diseases	ZIAAR041148
Defense Advanced Research Projects Agency	W911NF-11-2-0056

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Kieffer-Kwon, K. R., Tang, Z., Mathe, E., Qian, J., Sung, M. H., Li, G., Resch, W., Baek, S., Pruett, N., Grøntved, L., Vian, L., Nelson, S., Zare, H., Hakim, O., Reyon, D., Yamane, A., Nakahashi, H., Kovalchuk, A. L., Zou, J., ... Casellas, R. (2013). Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell, 155(7), 1507-1520. https://doi.org/10.1016/j.cell.2013.11.039

@article{d632f0e9f9094c54acd328c0974cf30a,

title = "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.",

author = "Kieffer-Kwon, {Kyong Rim} and Zhonghui Tang and Ewy Mathe and Jason Qian and Sung, {Myong Hee} and Guoliang Li and Wolfgang Resch and Songjoon Baek and Nathanael Pruett and Lars Gr{\o}ntved and Laura Vian and Steevenson Nelson and Hossein Zare and Ofir Hakim and Deepak Reyon and Arito Yamane and Hirotaka Nakahashi and Kovalchuk, {Alexander L.} and Jizhong Zou and Joung, {J. Keith} and Vittorio Sartorelli and Wei, {Chia Lin} and Xiaoan Ruan and Hager, {Gordon L.} and Yijun Ruan and Rafael Casellas",

note = "Funding Information: We thank Kefei Yu for CH12 cells and protocols; J. Simone and J. Lay for cell sorting; G. Gutierrez for technical assistance with Illumina analyzer. This work was supported by the Intramural Research Program of NIAMS and NCI, and internal Jackson Laboratory fund JAX19020120 to Y.R. J.K.J. was supported by NIH grants DP1 GM105378 and P50 HG005550, the Defense Advanced Research Projects Agency grant W911NF-11-2-0056 and The Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.Q. was supported by the NIH UGSP program. All animal experiments were performed according to NIH guidelines. High-performance computation was performed using NIH Helix Systems ( http://helix.nih.gov ). J.K.J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.{\textquoteright}s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. ",

year = "2013",

month = dec,

day = "19",

doi = "10.1016/j.cell.2013.11.039",

language = "אנגלית",

volume = "155",

pages = "1507--1520",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "7",

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Kieffer-Kwon, KR, Tang, Z, Mathe, E, Qian, J, Sung, MH, Li, G, Resch, W, Baek, S, Pruett, N, Grøntved, L, Vian, L, Nelson, S, Zare, H, Hakim, O, Reyon, D, Yamane, A, Nakahashi, H, Kovalchuk, AL, Zou, J, Joung, JK, Sartorelli, V, Wei, CL, Ruan, X, Hager, GL, Ruan, Y & Casellas, R 2013, 'Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation', Cell, vol. 155, no. 7, pp. 1507-1520. https://doi.org/10.1016/j.cell.2013.11.039

TY - JOUR

T1 - Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation

AU - Kieffer-Kwon, Kyong Rim

AU - Tang, Zhonghui

AU - Mathe, Ewy

AU - Qian, Jason

AU - Sung, Myong Hee

AU - Li, Guoliang

AU - Resch, Wolfgang

AU - Baek, Songjoon

AU - Pruett, Nathanael

AU - Grøntved, Lars

AU - Vian, Laura

AU - Nelson, Steevenson

AU - Zare, Hossein

AU - Hakim, Ofir

AU - Reyon, Deepak

AU - Yamane, Arito

AU - Nakahashi, Hirotaka

AU - Kovalchuk, Alexander L.

AU - Zou, Jizhong

AU - Joung, J. Keith

AU - Sartorelli, Vittorio

AU - Wei, Chia Lin

AU - Ruan, Xiaoan

AU - Hager, Gordon L.

AU - Ruan, Yijun

AU - Casellas, Rafael

N1 - Funding Information: We thank Kefei Yu for CH12 cells and protocols; J. Simone and J. Lay for cell sorting; G. Gutierrez for technical assistance with Illumina analyzer. This work was supported by the Intramural Research Program of NIAMS and NCI, and internal Jackson Laboratory fund JAX19020120 to Y.R. J.K.J. was supported by NIH grants DP1 GM105378 and P50 HG005550, the Defense Advanced Research Projects Agency grant W911NF-11-2-0056 and The Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.Q. was supported by the NIH UGSP program. All animal experiments were performed according to NIH guidelines. High-performance computation was performed using NIH Helix Systems ( http://helix.nih.gov ). J.K.J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

PY - 2013/12/19

Y1 - 2013/12/19

N2 - 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.

AB - 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.

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ER -

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

Abstract

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