The human mucin MUC4 is transcriptionally regulated by caudal-related homeobox, hepatocyte nuclear factors, forkhead box A, and GATA endodermal transcription factors in epithelial cancer cells.
The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell- and tissue-specific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell co-transfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1 alpha and -1 beta, FOXA1/A2, HNF-4 alpha and -4 gamma, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays. Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair.
Jonckheere
Nicolas
N
INSERM, U560, Place de Verdun, Lille, F-59045, France.
Vincent
Audrey
A
Perrais
Michaël
M
Ducourouble
Marie-Paule
MP
Male
Anita Korteland-van
AK
Aubert
Jean-Pierre
JP
Pigny
Pascal
P
Carraway
Kermit L
KL
Freund
Jean-Noël
JN
Renes
Ingrid B
IB
Van Seuningen
Isabelle
I
D000818:Animals; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D005260:Female; D050980:GATA Transcription Factors / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051536:Hepatocyte Nuclear Factors / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D055264:Mucin-4; D009077:Mucins / Q000737:chemistry* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D050980:GATA Transcription Factors; D050991:GATA4 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; D051536:Hepatocyte Nuclear Factors; D018398:Homeodomain Proteins; C524658:MUC4 protein, human; C524659:Muc4 protein, mouse; D055264:Mucin-4; D009077:Mucins; D014157:Transcription Factors