Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

Bjørt K. Kragesteen; Malte Spielmann; Christina Paliou; Verena Heinrich; Robert Schöpflin; Andrea Esposito; Carlo Annunziatella; Simona Bianco; Andrea M. Chiariello; Ivana Jerković; Izabela Harabula; Philine Guckelberger; Michael Pechstein; Lars Wittler; Wing Lee Chan; Martin Franke; Darío G. Lupiáñez; Katerina Kraft; Bernd Timmermann; Martin Vingron; Axel Visel; Mario Nicodemi; Stefan Mundlos; Guillaume Andrey

doi:10.1038/s41588-018-0221-x

Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

Bjørt K. Kragesteen, Malte Spielmann, Christina Paliou, Verena Heinrich, Robert Schöpflin, Andrea Esposito, Carlo Annunziatella, Simona Bianco, Andrea M. Chiariello, Ivana Jerković, Izabela Harabula, Philine Guckelberger, Michael Pechstein, Lars Wittler, Wing Lee Chan, Martin Franke, Darío G. Lupiáñez, Katerina Kraft, Bernd Timmermann, Martin VingronAxel Visel, Mario Nicodemi, Stefan Mundlos^*, Guillaume Andrey

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Humangenetik

151 Zitate (Scopus)

Abstract

The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.

Originalsprache	Englisch
Zeitschrift	Nature Genetics
Jahrgang	50
Ausgabenummer	10
Seiten (von - bis)	1463-1473
Seitenumfang	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0221-x
Publikationsstatus	Veröffentlicht - 01.10.2018

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We thank Judith Fiedler, Niclas Engemann and Karol Macura from the transgenic facility, Norbert Brieske for the WISH, and Myriam Hochradel from the sequencing core facility of the MPIMG. This study was supported by grants from the Deutsche Forschungsgemeinschaft (SP1532/2-1, MU 880/14) to M.S. and S.M., as well as the Max Planck Foundation to S.M. G.A. was supported by an early and advanced postdoc mobility grant from the Swiss National Science Foundation (P300PA_160964, P2ELP3_151960). M.N. acknowledges grants from the National Institutes of Health (NIH) (1U54DK107977-01), CINECA ISCRA (HP10CRTY8P), the Einstein BIH Fellowship Award (EVF-BIH-2016-282), and computer resources from the Istituto Nazionale di Fisica Nucleare, CINECA, and SCoPE at the University of Naples. A.V. was supported by NIH grants R01HG003988, U54HG006997, R24HL123879, and UM1HL098166. Work at the Lawrence Berkeley National Laboratory was performed under Department of Energy Contract DE-AC02-05CH11231, University of California.

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10.1038/s41588-018-0221-x

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Kragesteen, B. K., Spielmann, M., Paliou, C., Heinrich, V., Schöpflin, R., Esposito, A., Annunziatella, C., Bianco, S., Chiariello, A. M., Jerković, I., Harabula, I., Guckelberger, P., Pechstein, M., Wittler, L., Chan, W. L., Franke, M., Lupiáñez, D. G., Kraft, K., Timmermann, B., ... Andrey, G. (2018). Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis. Nature Genetics, 50(10), 1463-1473. https://doi.org/10.1038/s41588-018-0221-x

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title = "Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis",

abstract = "The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.",

author = "Kragesteen, \{Bj{\o}rt K.\} and Malte Spielmann and Christina Paliou and Verena Heinrich and Robert Sch{\"o}pflin and Andrea Esposito and Carlo Annunziatella and Simona Bianco and Chiariello, \{Andrea M.\} and Ivana Jerkovi{\'c} and Izabela Harabula and Philine Guckelberger and Michael Pechstein and Lars Wittler and Chan, \{Wing Lee\} and Martin Franke and Lupi{\'a}{\~n}ez, \{Dar{\'i}o G.\} and Katerina Kraft and Bernd Timmermann and Martin Vingron and Axel Visel and Mario Nicodemi and Stefan Mundlos and Guillaume Andrey",

note = "Funding Information: We thank Judith Fiedler, Niclas Engemann and Karol Macura from the transgenic facility, Norbert Brieske for the WISH, and Myriam Hochradel from the sequencing core facility of the MPIMG. This study was supported by grants from the Deutsche Forschungsgemeinschaft (SP1532/2-1, MU 880/14) to M.S. and S.M., as well as the Max Planck Foundation to S.M. G.A. was supported by an early and advanced postdoc mobility grant from the Swiss National Science Foundation (P300PA\_160964, P2ELP3\_151960). M.N. acknowledges grants from the National Institutes of Health (NIH) (1U54DK107977-01), CINECA ISCRA (HP10CRTY8P), the Einstein BIH Fellowship Award (EVF-BIH-2016-282), and computer resources from the Istituto Nazionale di Fisica Nucleare, CINECA, and SCoPE at the University of Naples. A.V. was supported by NIH grants R01HG003988, U54HG006997, R24HL123879, and UM1HL098166. Work at the Lawrence Berkeley National Laboratory was performed under Department of Energy Contract DE-AC02-05CH11231, University of California. Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

month = oct,

day = "1",

doi = "10.1038/s41588-018-0221-x",

language = "English",

volume = "50",

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Kragesteen, BK, Spielmann, M, Paliou, C, Heinrich, V, Schöpflin, R, Esposito, A, Annunziatella, C, Bianco, S, Chiariello, AM, Jerković, I, Harabula, I, Guckelberger, P, Pechstein, M, Wittler, L, Chan, WL, Franke, M, Lupiáñez, DG, Kraft, K, Timmermann, B, Vingron, M, Visel, A, Nicodemi, M, Mundlos, S & Andrey, G 2018, 'Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis', Nature Genetics, Jg. 50, Nr. 10, S. 1463-1473. https://doi.org/10.1038/s41588-018-0221-x

TY - JOUR

T1 - Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

AU - Kragesteen, Bjørt K.

AU - Spielmann, Malte

AU - Paliou, Christina

AU - Heinrich, Verena

AU - Schöpflin, Robert

AU - Esposito, Andrea

AU - Annunziatella, Carlo

AU - Bianco, Simona

AU - Chiariello, Andrea M.

AU - Jerković, Ivana

AU - Harabula, Izabela

AU - Guckelberger, Philine

AU - Pechstein, Michael

AU - Wittler, Lars

AU - Chan, Wing Lee

AU - Franke, Martin

AU - Lupiáñez, Darío G.

AU - Kraft, Katerina

AU - Timmermann, Bernd

AU - Vingron, Martin

AU - Visel, Axel

AU - Nicodemi, Mario

AU - Mundlos, Stefan

AU - Andrey, Guillaume

N1 - Funding Information: We thank Judith Fiedler, Niclas Engemann and Karol Macura from the transgenic facility, Norbert Brieske for the WISH, and Myriam Hochradel from the sequencing core facility of the MPIMG. This study was supported by grants from the Deutsche Forschungsgemeinschaft (SP1532/2-1, MU 880/14) to M.S. and S.M., as well as the Max Planck Foundation to S.M. G.A. was supported by an early and advanced postdoc mobility grant from the Swiss National Science Foundation (P300PA_160964, P2ELP3_151960). M.N. acknowledges grants from the National Institutes of Health (NIH) (1U54DK107977-01), CINECA ISCRA (HP10CRTY8P), the Einstein BIH Fellowship Award (EVF-BIH-2016-282), and computer resources from the Istituto Nazionale di Fisica Nucleare, CINECA, and SCoPE at the University of Naples. A.V. was supported by NIH grants R01HG003988, U54HG006997, R24HL123879, and UM1HL098166. Work at the Lawrence Berkeley National Laboratory was performed under Department of Energy Contract DE-AC02-05CH11231, University of California. Publisher Copyright: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.

AB - The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.

UR - https://www.scopus.com/pages/publications/85054029488

U2 - 10.1038/s41588-018-0221-x

DO - 10.1038/s41588-018-0221-x

M3 - Journal articles

C2 - 30262816

AN - SCOPUS:85054029488

SN - 1061-4036

VL - 50

SP - 1463

EP - 1473

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

Abstract

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