Human stem cell cultures from cleft lip/palate patients show enrichment of transcripts involved in extracellular matrix modeling by comparison to controls.
Nonsyndromic cleft lip and palate (NSCL/P) is a complex disease resulting from failure of fusion of facial primordia, a complex developmental process that includes the epithelial-mesenchymal transition (EMT). Detection of differential gene transcription between NSCL/P patients and control individuals offers an interesting alternative for investigating pathways involved in disease manifestation. Here we compared the transcriptome of 6 dental pulp stem cell (DPSC) cultures from NSCL/P patients and 6 controls. Eighty-seven differentially expressed genes (DEGs) were identified. The most significant putative gene network comprised 13 out of 87 DEGs of which 8 encode extracellular proteins: ACAN, COL4A1, COL4A2, GDF15, IGF2, MMP1, MMP3 and PDGFa. Through clustering analyses we also observed that MMP3, ACAN, COL4A1 and COL4A2 exhibit co-regulated expression. Interestingly, it is known that MMP3 cleavages a wide range of extracellular proteins, including the collagens IV, V, IX, X, proteoglycans, fibronectin and laminin. It is also capable of activating other MMPs. Moreover, MMP3 had previously been associated with NSCL/P. The same general pattern was observed in a further sample, confirming involvement of synchronized gene expression patterns which differed between NSCL/P patients and controls. These results show the robustness of our methodology for the detection of differentially expressed genes using the RankProd method. In conclusion, DPSCs from NSCL/P patients exhibit gene expression signatures involving genes associated with mechanisms of extracellular matrix modeling and palate EMT processes which differ from those observed in controls. This comparative approach should lead to a more rapid identification of gene networks predisposing to this complex malformation syndrome than conventional gene mapping technologies.
Human Genome Research Center, Biosciences Institute of University of Sao Paulo (USP), Sao Paulo, Sao Paulo, Brazil.
Daniela Franco
DF
Bueno
Daniele Yumi
DY
Sunaga
Gerson Shigeru
GS
Kobayashi
Meire
M
Aguena
Cassio Eduardo
CE
Raposo-Amaral
Cibele
C
Masotti
Lucas Alvizi
LA
Cruz
Peter Lees
PL
Pearson
Maria Rita
MR
Passos-Bueno
D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics / Q000473:pathology*; D002972:Cleft Palate / Q000235:genetics / Q000473:pathology*; D016000:Cluster Analysis; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D020411:Oligonucleotide Array Sequence Analysis; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
C085811:COL15A1 protein, human; D016326:Extracellular Matrix Proteins; D003094:Collagen; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D000626:Aminopeptidases; C503944:ERAP2 protein, human