Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes.
Fli1 is an Ets family member that is essential for embryonic development. Increasing evidence suggests modulating Fli1 gene expression impacts lymphocyte development/function and is an important mediator in the autoimmune disease lupus. Fli1 is over-expressed in splenic lymphocytes in lupus prone mouse strains and in PBMCs of lupus patients. Presently, it is unknown how Fli1 gene expression is controlled in lymphocytes or how it becomes over-expressed in lupus. Therefore, we examined Fli1 regulation in a murine B cell line and T cell line and identified several cis-regulatory elements within a 230 bp region that contribute to Fli1 promoter activity. Ets factors Elf1, Tel and Fli1 bind in vitro to this region and increase endogenous Fli1 expression when over-expressed in a T cell line. In addition, we determined that a microsatellite located adjacent to the region containing these cis-regulatory elements is polymorphic in three lupus prone mouse strains and that the length of the microsatellite is inversely correlated with promoter activity in a T cell line. These results suggest that several Ets factors, including Fli1 itself, are involved in the transcriptional regulation of Fli1 in lymphocytes. Furthermore, the presence of a polymorphic microsatellite in the Fli1 promoter may contribute to increased Fli1 expression in T cells during lupus disease progression.
Nowling
Tamara K
TK
Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Ste 912 CSB, Charleston, SC 29425, USA. nowling@musc.edu
Fulton
Jennifer Dziadyk
JD
Chike-Harris
Katherine
K
Gilkeson
Gary S
GS
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D050980:GATA Transcription Factors / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D050980:GATA Transcription Factors; D009687:Nuclear Proteins; D051789:Proto-Oncogene Protein c-fli-1; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D050791:STAT Transcription Factors; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C512896:Elf1 protein, mouse