Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions.
The fibrillins and latent transforming growth factor binding proteins (LTBPs) form a superfamily of extracellular matrix (ECM) proteins characterized by the presence of a unique domain, the 8-cysteine transforming growth factor beta (TGFβ) binding domain. These proteins are involved in the structure of the extracellular matrix and controlling the bioavailability of TGFβ family members. Genes encoding these proteins show differential expression in mesenchymal cell types which synthesize the extracellular matrix. We have investigated the promoter regions of the seven gene family members using the FANTOM5 CAGE database for human. While the protein and nucleotide sequences show considerable sequence similarity, the promoter regions were quite diverse. Most genes had a single predominant transcription start site region but LTBP1 and LTBP4 had two regions initiating different transcripts. Most of the family members were expressed in a range of mesenchymal and other cell types, often associated with use of alternative promoters or transcription start sites within a promoter in different cell types. FBN3 was the lowest expressed gene, and was found only in embryonic and fetal tissues. The different promoters for one gene were more similar to each other in expression than to promoters of the other family members. Notably expression of all 22 LTBP2 promoters was tightly correlated and quite distinct from all other family members. We located candidate enhancer regions likely to be involved in expression of the genes. Each gene was associated with a unique subset of transcription factors across multiple promoters although several motifs including MAZ, SP1, GTF2I and KLF4 showed overrepresentation across the gene family. FBN1 and FBN2, which had similar expression patterns, were regulated by different transcription factors. This study highlights the role of alternative transcription start sites in regulating the tissue specificity of closely related genes and suggests that this important class of extracellular matrix proteins is subject to subtle regulatory variations that explain the differential roles of members of this gene family.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, UK. Electronic address: margaret.davis@roslin.ed.ac.uk.
Margaret R
MR
Davis
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark. Electronic address: robin@binf.ku.dk.
Robin
R
Andersson
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan(1); RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: severin@gsc.rkien.jp.
Jessica
J
Severin
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan(1); RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: mdehoon@gsc.riken.jp.
Michiel
M
de Hoon
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan(1); RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: nbertin@gsc.riken.jp.
Nicolas
N
Bertin
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, UK. Electronic address: kennethbaillie@gmail.com.
J Kenneth
JK
Baillie
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan(1); RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan. Electronic address: kawaji@gsc.riken.jp.
Hideya
H
Kawaji
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark. Electronic address: albin@binf.ku.dk.
Albin
A
Sandelin
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan(1); RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan. Electronic address: forrest@gsc.riken.jp.
Alistair R R
AR
Forrest
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, UK; The University of Queensland Northside Clinical School, Prince Charles Hospital, Chermside 4032, Australia. Electronic address: kim.summers@roslin.ed.ac.uk.
Kim M
KM
Summers
D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D020869:Gene Expression Profiling; D006801:Humans; D000090062:Kruppel-Like Factor 4; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D054392:Adipokines
D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D000090062:Kruppel-Like Factor 4; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000715467:KLF4 protein, human
Extracellular matrix; Fibrillin; Gene regulation; Latent transforming growth factor β binding protein; Promoter; Transcription start sites