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The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

Namit Kumar, Yu-Hwai Tsai, Lei Chen, Anbo Zhou, Kushal K. Banerjee, Madhurima Saxena, Sha Huang, Jinchuan Xing, Ramesh A. Shivdasani, Jason R. Spence, View ORCID ProfileMichael P. Verzi
doi: https://doi.org/10.1101/425827
Namit Kumar
1Rutgers, the State University of New Jersey, Department of Genetics
2Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
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Yu-Hwai Tsai
3Department of Internal Medicine
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Lei Chen
1Rutgers, the State University of New Jersey, Department of Genetics
2Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
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Anbo Zhou
1Rutgers, the State University of New Jersey, Department of Genetics
2Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
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Kushal K. Banerjee
7Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
8Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA
9Harvard Stem Cell Institute, Cambridge, MA 02139, USA
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Madhurima Saxena
7Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
8Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA
9Harvard Stem Cell Institute, Cambridge, MA 02139, USA
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Sha Huang
3Department of Internal Medicine
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Jinchuan Xing
1Rutgers, the State University of New Jersey, Department of Genetics
2Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
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Ramesh A. Shivdasani
7Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
8Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA
9Harvard Stem Cell Institute, Cambridge, MA 02139, USA
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Jason R. Spence
3Department of Internal Medicine
6Department of Biomedical Engineering University of Michigan College of Engineering, Ann Arbor, MI 48109, USA
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  • For correspondence: spencejr@med.umich.edu Verzi@biology.rutgers.edu
Michael P. Verzi
1Rutgers, the State University of New Jersey, Department of Genetics
2Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
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  • ORCID record for Michael P. Verzi
  • For correspondence: spencejr@med.umich.edu Verzi@biology.rutgers.edu
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Abstract

Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic-loss of CDX2 triggers homeotic transformation of intestinal fate, while adult-onset Cdx2-loss compromises critical physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program, but rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or maturity. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 24, 2018.
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The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development
Namit Kumar, Yu-Hwai Tsai, Lei Chen, Anbo Zhou, Kushal K. Banerjee, Madhurima Saxena, Sha Huang, Jinchuan Xing, Ramesh A. Shivdasani, Jason R. Spence, Michael P. Verzi
bioRxiv 425827; doi: https://doi.org/10.1101/425827
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The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development
Namit Kumar, Yu-Hwai Tsai, Lei Chen, Anbo Zhou, Kushal K. Banerjee, Madhurima Saxena, Sha Huang, Jinchuan Xing, Ramesh A. Shivdasani, Jason R. Spence, Michael P. Verzi
bioRxiv 425827; doi: https://doi.org/10.1101/425827

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