한빛사논문
- 조회775
Ricardo Linares-Saldana1,2,3,13, Wonho Kim1,2,3,13, Nikhita A. Bolar1,2,3,13, Haoyue Zhang4,5, Bailey A. Koch-Bojalad1,2,3, Sora Yoon1,3,6,7, Parisha P. Shah1,2,3, Ashley Karnay1,2,3, Daniel S. Park1,3,6, Jennifer M. Luppino1,3,6, Son C. Nguyen1,3,6, Arun Padmanabhan8,9, Cheryl L. Smith1,2,3, Andrey Poleshko1,2,3, Qiaohong Wang1,2,3, Li Li1,2,3, Deepak Srivastava8,10, Golnaz Vahedi1,3,6,7,11, Gwang Hyeon Eom1,2,3,12, Gerd A. Blobel 1,3,5, Eric F. Joyce1,3,6 and Rajan Jain1,2,3,*
1Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2Department of Cell and Developmental Biology, Department of Medicine, Institute of Regenerative Medicine, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA. 3Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA. 4Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China. 5Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 6Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. 7Institute for Immunology, Epigenetics Institute, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA. 8Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA. 9Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA. 10Roddenberry Stem Cell Center at the Gladstone Institutes, Departments of Pediatrics and Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, USA. 11Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. 12Department of Pharmacology, Chonnam National University Medical School, Hwasun, Republic of Korea. 13These authors contributed equally: Ricardo Linares-Saldana, Wonho Kim, Nikhita A. Bolar.
*Corresponding author
Abstract
Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the importance of genome folding in neural crest progenitor differentiation. Brd4 deletion in neural crest results in cohesinopathy-like phenotypes. BRD4 interacts with NIPBL, a cohesin agonist, and BRD4 depletion or loss of the BRD4–NIPBL interaction reduces NIPBL occupancy, suggesting that BRD4 stabilizes NIPBL on chromatin. Chromatin interaction mapping and imaging experiments demonstrate that BRD4 depletion results in compromised genome folding and loop extrusion. Finally, mutation of individual BRD4 amino acids that mediate an interaction with NIPBL impedes neural crest differentiation into smooth muscle. Remarkably, loss of WAPL, a cohesin antagonist, rescues attenuated smooth muscle differentiation resulting from BRD4 loss. Collectively, our data reveal that BRD4 choreographs genome folding and illustrates the relevance of balancing cohesin activity for progenitor differentiation.
논문정보
- Research article
- 2021년 10월 (BRIC 등록일 2021-10-12)
- 국내+국외 연구진
- 생명과학 > 세포생물학
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