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Cell Rep. 2015 Oct 13;13(2):337-49. doi: 10.1016/j.celrep.2015.08.075. Epub 2015 Sep 24.

Chromatin Architecture of the Pitx2 Locus Requires CTCF- and Pitx2-Dependent Asymmetry that Mirrors Embryonic Gut Laterality.

Author information

1
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
2
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
3
The Jackson Laboratory, Bar Harbor, ME, 04609, USA; Eastern Maine Medical Center Cancer Care, 33 Whiting Hill Road, Brewer, ME 04412, USA.
4
Department of Biomedical Sciences, The Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853, USA.
5
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Heart Institute, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Electronic address: nk378@cornell.edu.

Abstract

Expression of Pitx2 on the left side of the embryo patterns left-right (LR) organs including the dorsal mesentery (DM), whose asymmetric cell behavior directs gut looping. Despite the importance of organ laterality, chromatin-level regulation of Pitx2 remains undefined. Here, we show that genes immediately neighboring Pitx2 in chicken and mouse, including a long noncoding RNA (Pitx2 locus-asymmetric regulated RNA or Playrr), are expressed on the right side and repressed by Pitx2. CRISPR/Cas9 genome editing of Playrr, 3D fluorescent in situ hybridization (FISH), and variations of chromatin conformation capture (3C) demonstrate that mutual antagonism between Pitx2 and Playrr is coordinated by asymmetric chromatin interactions dependent on Pitx2 and CTCF. We demonstrate that transcriptional and morphological asymmetries driving gut looping are mirrored by chromatin architectural asymmetries at the Pitx2 locus. We propose a model whereby Pitx2 auto-regulation directs chromatin topology to coordinate LR transcription of this locus essential for LR organogenesis.

PMID:
26411685
PMCID:
PMC4617833
DOI:
10.1016/j.celrep.2015.08.075
[Indexed for MEDLINE]
Free PMC Article

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