Identification of key genes in cleft lip with or without cleft palate regulated by miR-199a-5p
Introduction
Cleft lip with or without cleft palate (CL/P) is the most common form of birth defect in humans, occurring frequently in Amerindians and Asians [1]. Approximately 70% of oral clefts exist as a non-syndromic form, and the remaining 30% are related to Mendelian disorders or teratogenic, chromosomal and sporadic conditions. The incidence is about 1.82 per 1000 live births in China, while the global incidence of CL/P is estimated to be 1.43 per 1,000, with a wide variability among ethnic groups and regions [2]. Clinically, CL/P causes facial deformity in children. The anomaly influences sucking, swallowing and speaking. Furthermore, individuals with CL/P have higher morbidity and mortality throughout life than do unaffected children [3]. Therefore, CL/P is a major public health problem having direct impacts on the health of children and the quality of life.
The etiology of CL/P involves complicated heredity and environmental factors, such as geographic origin, genetics and socioeconomic status. Gene-environment and/or gene-gene interactions may contribute to CL/P. Some gene positions in different chromosomal regions and genes related to CL/P have been reported from association and linkage analysis [4].
MicroRNAs (miRNAs) are kinds of small non-coding RNAs that regulate embryonic development by binding to mRNAs to control their post-transcriptional expression and inhibit their translation, leading to the destabilization of their target mRNAs [5]. The roles of miRNAs in cell differentiation and embryonic development were investigated in the past few years [6]. Increasing evidences suggest that miRNAs are functionally important for the regulation of CL/P [7,8]. The genetic variants of miRNA processing genes such as DROSHA may increase the risk of CL/P [9]. MiRNA-mRNA interactions play a crucial role in orofacial development. However, these interactions may be influenced by genetic variations in the 3′-UTR of human genes that can alter the thermodynamic interplay between them. For instance, L. Ma et al. found that miRNA-binding single nucleotide polymorphism (SNPs) of MSX1 is associated with the increased risk of CLP in Chinese Han population [5].
The miRNA-199a hairpin precursor gene is located on human chromosome19, and its orthologous gene resides on mouse chromosome 9 [10]. Previous studies have revealed that miR-199a-5p play an important role in various biological processes including development, growth, the response to hypoxia and anti-cancer effect [11,12]. Evidence has been found that miR-199a-5p may be associated with CL/P [13]. The expression of miR-199a-5p has been found to increase with the development of the upper lip of mice [14]. Hai-Lei Ding et al. carried out miRNA sequencing on miRNAs extracted from mouse embryonic. The result demonstrated that miR-199a-5p was differentially expressed between palatal shelves, frontonasal prominence and maxillary prominence [15]. These studies indicate that miR-199a-5p may be associated with the formation of CL/P.
Whether the key genes regulated by miR-199a-5p are involved in CL/P has not yet been explored. This article primarily used bioinformatics to find the main genes of miR-199a-5p, and clarify the possible pathogenesis of the CL/P induced by miR-199a-5p.
Section snippets
The mature sequence of miR-199a-5p
MiR-199a-5p is from pre-miR-199a-1 and pre-miR-199a-2, which are transcribed from DNA sequences on different chromosomes. MiR-199a-5p is the highly homologous miRNA of miR-199 b-5p. In order to understand the mature sequences of miR-199a-5p and miR-199 b-5p, the miRBase (http://www.mirbase.org/) [16] and TargetScanhuman7.1 (http://www.targetscan.org/vert_71/) [17] were used. MiRNA research revealed different sets of miRNAs expressed in diverse cell types and tissues. Thus, the Human miRNA
Mature sequences of miR-199a-5p and the expression in tissues
The sequence and structure of miRNA can affect its function. MiR-199a-5p comes from two different pre-miR-199a-1 and pre-miR-199a-2, which are transcribed from DNA sequences on different chromosomes. Fig. 2A shows the mature sequences of miR-199a-5p and miR-199 b-5p, which are highly homologous. The picture showed that miR-199a-5p and miR-199 b-5p share common target gene and similar mature sequences. Therefore, it can be speculated that miR-199a-5p and miR-199 b-5p may have similar functions.
Discussion
Although a lot of studies focus on the etiology of CL/P, there are little research on the relationship between miRNAs and CL/P. Disorder of miRNAs conduces to pathogenesis of all kinds of human diseases [29]. Several studies have revealed that miR-199a-5p may increase the risk of CL/P. However, the genes regulated by miR-199a-5p which may mediate the occurrence of CL/P are still not clear. Therefore, we conducted this study by using bioinformatics.
Primary sequence determinants as well as
Conflicts of interest
The authors deny any conflicts of interest related to this study.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (No.81273103), the Education Department of Jiangsu Province (No. 16KJB330010), the China Postdoctoral Science Foundation funded project (No. 2016M601892) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
References (53)
- et al.
MSX1 gene polymorphisms in Mexican patients with non-syndromic cleft lip/palate
Int. J. Pediatr. Otorhinolaryngol.
(2016) - et al.
Identification of miR-199a-5p target genes in the skin keratinocyte and their expression in cutaneous squamous cell carcinoma
J. Dermatol. Sci.
(2015) - et al.
Role of angiogenesis-related genes in cleft lip/palate: review of the literature
Int. J. Pediatr. Otorhinolaryngol.
(2014) - et al.
MicroRNAs in stress signaling and human disease
Cell
(2012) - et al.
Muscle-specific microRNAs in skeletal muscle development
Dev. Biol.
(2016) - et al.
Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and Shh signaling
Dev. Biol.
(2008) - et al.
Innate lymphoid cells: a paradigm for low SSI in cleft lip repair
J. Surg. Res.
(2016) - et al.
Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation
J. Invest. Dermatol.
(2014) - et al.
Associations between microRNA binding site SNPs in FGFs and FGFRs and the risk of non-syndromic orofacial cleft
Sci. Rep.
(2016) - et al.
Clinical aspects associated with syndromic forms of orofacial clefts in a colombian population
Colomb. Medica Cali, Colomb.
(2015)
Clinical and epidemiologic studies of nonsyndromic cleft lip and palate in China: analysis of 4268 cases
Ann. Plast. Surg.
Are isolated facial cleft lip and palate associated with increased perinatal mortality? A cohort study from the West Midlands Region, 1995–1997
J. Matern. Neonatal Med
A miRNA-binding-site SNP of MSX1 is associated with NSOC susceptibility
J. Dent. Res.
MicroRNA functions in animal development and human disease
Development
Small players with a big role: MicroRNAs in pathophysiology of cleft lip and palate
Indian J. Hum. Genet.
Genetic variants of microRNA processing genes and risk of non-syndromic orofacial clefts
Oral Dis.
Mouse-specific up-regulation of Ccnb1 expression by miR-199a-5p in keratinocyte
FEBS Open Bio
MicroRNA-199a-5p regulates the proliferation of pulmonary microvascular endothelial cells in hepatopulmonary syndrome
Cell. Physiol. Biochem.
MicroRNAs in palatogenesis and cleft palate
Front. Physiol.
MicroRNA expression profiling of the developing murine upper lip
Dev. Growth Differ.
MicroRNA profiling during craniofacial development: potential roles for Mir23b and Mir133b
Front. Physiol.
MiRBase: annotating high confidence microRNAs using deep sequencing data
Nucleic Acids Res.
Predicting effective microRNA target sites in mammalian mRNAs
Elife
Distribution of miRNA expression across human tissues
Nucleic Acids Res.
DIANA-TarBase v7.0: indexing more than half a million experimentally supported miRNA:mRNA interactions
Nucleic Acids Res.
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