The lineage-specific transcription factor CDX2 navigates dynamic chromatin to control distinct stages of intestine development.
Animals
CDX2 Transcription Factor
/ genetics
CRISPR-Cas Systems
Cell Differentiation
Cell Lineage
Chromatin
/ metabolism
Female
Gene Expression Regulation, Developmental
Homeodomain Proteins
/ metabolism
Humans
Intestinal Mucosa
/ metabolism
Intestines
/ embryology
Mice
Mice, Knockout
Mutation
Pluripotent Stem Cells
/ cytology
Protein Binding
Protein Domains
Trans-Activators
/ metabolism
Chromatin
Development
Intestine
Lineage-specifying
Patterning
Transcription factor
Journal
Development (Cambridge, England)
ISSN: 1477-9129
Titre abrégé: Development
Pays: England
ID NLM: 8701744
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
25
09
2018
accepted:
30
01
2019
pubmed:
13
2
2019
medline:
31
12
2019
entrez:
13
2
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30745430
pii: dev.172189
doi: 10.1242/dev.172189
pmc: PMC6432663
pii:
doi:
Substances chimiques
CDX2 Transcription Factor
0
CDX2 protein, human
0
Cdx2 protein, mouse
0
Chromatin
0
Homeodomain Proteins
0
Trans-Activators
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : F32 DK115080
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK085532
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK085532
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082889
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190558
Pays : United States
Informations de copyright
© 2019. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing or financial interests.
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