Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions

Abstract

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.

Regulation of fibrillins and modulators of TGFβ in fetal bovine and human ovaries

“…This study was heavily biased to adult tissues present in the FANTOM database at that time, thus limiting the information about the promoter of FBN3 and identification of potential transcription factor-binding motifs present within this promoter. Interestingly, it was found that the transcription factor-binding motifs in the FBN3 promoter do not overlap with those of the other two fibrillin genes (Davis et al 2014). This would be consistent with the differential expression of the fibrillin genes seen in ovaries (Hatzirodos et al 2011).…”

“…These data therefore imply that the three fibrillin genes have independent regulatory mechanisms to account for their different expression profiles in the bovine and human. This is also supported by the study of Davis et al (2014), which found that there was little overlap in the transcription factor motifs present on the human FBN3 promoter and those of FBN1 and 2 promoters, suggesting that these genes are differentially regulated and differentially expressed (Davis et al 2014).…”

“…A recent study by Davis et al (2014) identified the promoters of the human fibrillin genes and the transcription factors that bind to these promoters (Davis et al 2014). This study was heavily biased to adult tissues present in the FANTOM database at that time, thus limiting the information about the promoter of FBN3 and identification of potential transcription factor-binding motifs present within this promoter.…”

LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy

“…Moreover, its silencing may ameliorate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling. The latent transforming growth factor binding proteins (LTBPs) are members of the extracellular matrix (ECM) protein fibrinogens, characterized by repetitive domain structures that include duplication of a calcium‐binding EGF‐like domain and an 8‐Cys/TGFβ binding domain . LTBPs were initially separated from the large latent complexes of TGF‐β, which was covalently associated with the TGF‐β propeptide via disulfide bonds, but are also linked to fibrillin microfibrils in the ECM .…”

Latent TGF-β-binding proteins

“…LTBP-1 is expressed in a variety of tissues and cell types (Davis et al 2014), but expression is particularly abundant in heart, lung, spleen, kidney and stomach (Tsuji et al 1990; Saharinen et al 1999). A number of splice forms have been described for LTBP-1 including a short (LTBP-1S) and long (LTBP-1L) form that utilize different transcriptional start sites (Figure 1).…”