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 - http://www.scopus.com/inward/record.url?scp=85054029488&partnerID=8YFLogxK
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 -
