A distant upstream locus control region is critical for expression of the Kit receptor gene in mast cells.
The Kit receptor tyrosine kinase functions in hematopoiesis, melanogenesis, and gametogenesis and in interstitial cells of Cajal. We previously identified two upstream hypersensitive site (HS) clusters in mast cells and melanocytes. Here we investigated the roles of these 5' HS sequences in Kit expression using transgenic mice carrying Kit-GFP reporter constructs. In these mice there is close correspondence between Kit-GFP reporter and endogenous Kit gene expression in most tissues analyzed. Deletion analysis defined the 5' upstream HS cluster region as critical for Kit expression in mast cells. Furthermore, chromatin immunoprecipitation analysis in mast cells showed that H3 and H4 histone hyperacetylation and RNA polymerase II recruitment within the Kit promoter and in the 5' HS region were associated with Kit expression. Therefore, the 5' upstream hypersensitivity sites appear to be critical components of locus control region-mediated Kit gene activation in mast cells.
Berrozpe
Georgina
G
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Agosti
Valter
V
Tucker
Christine
C
Blanpain
Cedric
C
Manova
Katia
K
Besmer
Peter
P
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006657:Histones / Q000378:metabolism; D019901:Locus Control Region; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009690:Nucleic Acid Conformation; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation
D002843:Chromatin; D006657:Histones; D011993:Recombinant Fusion Proteins; D019009:Proto-Oncogene Proteins c-kit; D012319:RNA Polymerase II