title: Kruppel-like factor4 regulatesPRDM1expression through binding to an autoimmune risk allele.
abstract: A SNP identified as rs548234, which is found inPRDM1, the gene that encodes BLIMP1, is a risk allele associated with systemic lupus erythematosus (SLE). BLIMP1 expression was reported to be decreased in women with thePRDM1rs548234 risk allele compared with women with the nonrisk allele in monocyte-derived DCs (MO-DCs). In this study, we demonstrate that BLIMP1 expression is regulated by the binding of Kruppel-like factor 4 (KLF4) to the risk SNP. KLF4 is highly expressed in MO-DCs but undetectable in B cells, consistent with the lack of altered expression of BLIMP1 in B cells from risk SNP carriers. Female rs548234 risk allele carriers, but not nonrisk allele carriers, exhibited decreased levels of BLIMP1 in MO-DCs, showing that the regulatory function of KLF4 is influenced by the risk allele. In addition, KLF4 directly recruits histone deacetylases (HDAC4, HDAC6, and HDAC7), established negative regulators of gene expression. Finally, the knock down of KLF4 expression reversed the inhibitory effects of the risk SNP on promoter activity and BLIMP1 expression. Therefore, the binding of KLF4 and the subsequent recruitment of HDACs represent a mechanism for reduced BLIMP1 expression in MO-DCs bearing the SLE risk allele rs548234.
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases and.
authors.forename: Su Hwa
authors.initials: SH
authors.lastname: Jang
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases and.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, New York, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases and.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases and.
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases