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Development. 2019 Mar 1;146(5). pii: dev172189. doi: 10.1242/dev.172189.

The lineage-specific transcription factor CDX2 navigates dynamic chromatin to control distinct stages of intestine development.

Kumar N1,2, Tsai YH3, Chen L1,2, Zhou A1,2, Banerjee KK4,5,6, Saxena M4,5,6, Huang S3, Toke NH1,2, Xing J1,2, Shivdasani RA4,5,6, Spence JR7,8,9,10, Verzi MP11,2.

Author information

1
Rutgers, the State University of New Jersey, Department of Genetics, Piscataway, NJ 08854, USA.
2
Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA.
3
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
4
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
6
Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
7
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA spencejr@med.umich.edu Verzi@biology.rutgers.edu.
8
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
9
Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
10
Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA.
11
Rutgers, the State University of New Jersey, Department of Genetics, Piscataway, NJ 08854, USA spencejr@med.umich.edu Verzi@biology.rutgers.edu.

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, whereas adult-onset loss compromises crucial 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; rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or mature intestinal function. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

KEYWORDS:

Chromatin; Development; Intestine; Lineage-specifying; Patterning; Transcription factor

PMID:
30745430
PMCID:
PMC6432663
[Available on 2020-03-01]
DOI:
10.1242/dev.172189

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