Hartman Institute for Therapeutic Organ Regeneration

Distinct functions are implicated for the GATA-4, -5, and -6 transcription factors in the regulation of intestine epithelial cell differentiation.

TitleDistinct functions are implicated for the GATA-4, -5, and -6 transcription factors in the regulation of intestine epithelial cell differentiation.
Publication TypeJournal Article
Year of Publication1998
AuthorsGao X, Sedgwick T, Shi YB, Evans T
JournalMol Cell Biol
Volume18
Issue5
Pagination2901-11
Date Published1998 May
ISSN0270-7306
KeywordsAnimals, Antigens, Differentiation, Base Sequence, Carrier Proteins, Cell Differentiation, Chick Embryo, DNA-Binding Proteins, Epithelial Cells, Fatty Acid-Binding Protein 7, Fatty Acid-Binding Proteins, Female, GATA4 Transcription Factor, GATA5 Transcription Factor, GATA6 Transcription Factor, Gene Expression Regulation, Developmental, Humans, Intestinal Mucosa, Molecular Sequence Data, Myelin P2 Protein, Neoplasm Proteins, Promoter Regions, Genetic, RNA, Messenger, Stem Cells, Transcription Factors, Tumor Suppressor Proteins
Abstract

Based on conserved expression patterns, three members of the GATA family of transcriptional regulatory proteins, GATA-4, -5, and -6, are thought to be involved in the regulation of cardiogenesis and gut development. Functions for these factors are known in the heart, but relatively little is understood regarding their possible roles in the regulation of gut-specific gene expression. In this study, we analyze the expression and function of GATA-4, -5, and -6 using three separate but complementary vertebrate systems, and the results support a function for these proteins in regulating the terminal-differentiation program of intestinal epithelial cells. We show that xGATA-4, -5, and -6 can stimulate directly activity of the promoter for the intestinal fatty acid-binding protein (xIFABP) gene, which is a marker for differentiated enterocytes. This is the first direct demonstration of a target for GATA factors in the vertebrate intestinal epithelium. Transactivation by xGATA-4, -5, and -6 is mediated at least in part by a defined proximal IFABP promoter element. The expression patterns for cGATA-4, -5, and -6 are markedly distinct along the proximal-distal villus axis. Transcript levels for cGATA-4 increase along the axis toward the villus tip; likewise, cGATA-5 transcripts are largely restricted to the distal tip containing differentiated cells. In contrast, the pattern of cGATA-6 transcripts is complementary to cGATA-5, with highest levels detected in the region of proliferating progenitor cells. Undifferentiated and proliferating human HT-29 cells express hGATA-6 but not hGATA-4 or hGATA-5. Upon stimulation to differentiate, the transcript levels for hGATA-5 increase, and this occurs prior to increased transcription of the terminal differentiation marker intestinal alkaline phosphatase. At the same time, hGATA-6 steady-state transcript levels decline appreciably. All of the data are consistent with evolutionarily conserved but distinct roles for these factors in regulating the differentiation program of intestinal epithelium. Based on this data, we suggest that GATA-6 might function primarily within the proliferating progenitor population, while GATA-4 and GATA-5 function during differentiation to activate terminal-differentiation genes including IFABP.

DOI10.1128/MCB.18.5.2901
Alternate JournalMol Cell Biol
PubMed ID9566909
PubMed Central IDPMC110669

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