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Nat Genet. 2018 Oct;50(10):1463-1473. doi: 10.1038/s41588-018-0221-x. Epub 2018 Sep 27.

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

Author information

1
RG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
2
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
3
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
4
Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
5
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
6
Dipartimento di Fisica, Università di Napoli Federico II, and Istituto Nazionale di Fisica Nucleare, Napoli, Complesso Universitario di Monte Sant'Angelo, Naples, Italy.
7
Berlin Institute of Health, MDC-Berlin, Berlin, Germany.
8
Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
9
Epigenetics and Sex Development Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
10
Max Planck Institute for Molecular Genetics, Sequencing Core Facility, Berlin, Germany.
11
Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
12
U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
13
School of Natural Sciences, University of California, Merced, CA, USA.
14
Dipartimento di Fisica, Università di Napoli Federico II, and Istituto Nazionale di Fisica Nucleare, Napoli, Complesso Universitario di Monte Sant'Angelo, Naples, Italy. nicodem@na.infn.it.
15
Berlin Institute of Health, MDC-Berlin, Berlin, Germany. nicodem@na.infn.it.
16
RG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. mundlos@molgen.mpg.de.
17
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany. mundlos@molgen.mpg.de.
18
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany. mundlos@molgen.mpg.de.
19
RG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. andrey@molgen.mpg.de.
20
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany. andrey@molgen.mpg.de.
21
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany. andrey@molgen.mpg.de.

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.

PMID:
30262816
DOI:
10.1038/s41588-018-0221-x

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