Expression profiling of transforming growth factor β superfamily genes in developing orofacial tissue

Mukhopadhyay, Partha; Greene, Robert M.; Pisano, M. Michele

doi:10.1002/bdra.20276

Cited by 13 publications

(28 citation statements)

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“…To begin to address the role of epigenetics in regulating ontogenesis of the secondary palate, we conducted a study that identified differentially expressed mRNAs in the murine developing palate (GD12–GD14) [14]. Using high-density microarray-based mRNA profiling, a number of differentially expressed genes, including Sox4 , were identified.…”

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confidence: 99%

Epigenetic Regulation of Sox4 during Palate Development

et al. 2013

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Aim Identification of genes that contribute to secondary palate development provide a better understanding of the etiology of palatal clefts. Gene-expression profiling of the murine palate from gestational days 12–14 (GD12–14), a critical period in palate development, identified Sox4 as a differentially expressed gene. In this study, we have examined if the differential expression of Sox4 in the palate is due to changes in DNA methylation. Materials & methods In situ hybridization analysis was used to localize the expression of Sox4 in the developing murine secondary palate. CpG methylation profiling of a 1.8-kb upstream region of Sox4 in the secondary palate from GD12–14 and transfection analysis in murine embryonic maxillary mesenchymal cells using Sox4 deletion, mutant and in vitro methylated plasmid constructs were used to identify critical CpG residues regulating Sox4 expression in the palate. Results Spatiotemporal analysis revealed that Sox4 is expressed in the medial edge epithelium and presumptive rugae-forming regions of the palate from GD12 to GD13. Following palatal shelf fusion on GD14, Sox4 was expressed exclusively in the epithelia of the palatal rugae, structures that serve as signaling centers for the anteroposterior extension of the palate, and that are thought to serve as neural stem cell niches. Methylation of a 1.8-kb region upstream of Sox4, containing the putative promoter, completely eliminated promoter activity. CpG methylation profiling of the 1.8-kb region identified a CpG-poor region (DMR4) that exhibited significant differential methylation during palate development, consistent with changes in Sox4 mRNA expression. Changes in the methylation of DMR4 were attributed primarily to CpGs 83 and 85. Conclusion Our studies indicate that Sox4 is an epigenetically regulated gene that likely integrates multiple signaling systems for mediating palatal fusion, palatal extension and/or the maintenance of the neural stem cell niche in the rugae.

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confidence: 99%

Epigenetic Regulation of Sox4 during Palate Development

et al. 2013

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“…On the other hand, the proximal DMR (amplicon 3) contained CpG residues that showed a signifi cant decrease in methylation from GD 12 to GD 13, which was inconsistent with decreasing Sox4 mRNA levels detected in the secondary palate (Mukhopadhyay et al 2006a). Efforts are now underway to assess the functional relevance of these CpG residues in Sox4 expression in the palate.…”

Section: The Sox4 Paradigmmentioning

confidence: 94%

“…Failure to establish correct methylation patterns can lead to embryonic lethality (Li et al 1992) or can result in developmental craniofacial malformations (Abu-Amero et al 2008;Gonzales et al 2005;Kakutani et al 1996;Matsuda and Yasutomi 1992;Ohgane et al 2001) including CP (Bliek et al 2008;Kuriyama et al 2008;Loenarz et al 2010). Previous studies in our laboratory, utilizing messenger RNA (mRNA 1 )-based microarray analysis, have demonstrated the expression of a number of methyltransferases and methyl-CpG binding proteins in GD 9.5 murine embryonic craniofacial tissue (Mukhopadhyay et al 2006a). This provides evidence that DNA methylation is a dynamic process occurring during secondary palate development.…”

Section: Basic Features and Current Conceptsmentioning

confidence: 94%

“…Sox4 is a transcription factor belonging to the SoxC family and is functionally associated with the TGFß and Wnt-ß-catenin signaling pathways (Scharer et al 2009). Signifi cant downregulation of Sox4 gene expres sion occurs in developing palatal tissue between GD 12 and GD 13 and remains steady thereafter from GD 13 to GD 14 (Mukhopadhyay et al 2006a). This expression pattern could be due to critical CpG residues in the upstream regulatory region of Sox4 becoming increasingly methylated from GD 12 to GD 13.…”

Section: The Sox4 Paradigmmentioning

confidence: 96%

“…Lately, an intriguing hint that polymorphisms in human miRNA-coding genes might underlie the etiology of CP was presented by the association of an SNP in the human gene encoding miR-140 with isolated CP in a small cohort from western China ). An array of morphogens, growth factors, and signaling mediators, such as members of the TGFß family, bone morphogenetic proteins (BMPs 1 ), Wnts, Shh, epidermal growth factor, mitogenactivated protein kinases, cyclic adenosine monophosphate (cAMP), and retinoic acid, as well as a variety of downstream transcription factors, such as Sma and MAD related family proteins (Smads), cAMP response element-binding protein (CREB), CREB binding protein, E1A binding protein p300, Sloan-Kettering Institute protein (Ski), Ski-related novel protein N, nuclear receptor corepressors, and histone deacetylases, have been reported to interact and coordinate the dynamic process of orofacial ontogenesis (Brunet et al 1995;Gehris and Greene 1992;Lan et al 2006;Mendelsohn et al 1994;Mukhopadhyay et al 2006aMukhopadhyay et al , 2006bWarner et al 2002;Weston et al 1998). Many of the aforementioned signaling mediators and transcriptional regulators have been shown to be targeted by an ever-growing number of miRNAs (Kawasaki and Taira 2003;Kennell et al 2008;Li and Carthew 2005;Lin et al 2009;Martello et al 2007;Zhao et al 2008).…”

Section: Microrna Gene Expression Signature Of the Developing Orofacimentioning

confidence: 98%

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Developmental Epigenetics of the Murine Secondary Palate

Seelan¹,

Mukhopadhyay²,

Pisano³

et al. 2012

ILAR Journal

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Orofacial clefts occur with a frequency of 1 to 2 per 1000 live births. Cleft palate, which accounts for 30% of orofacial clefts, is caused by the failure of the secondary palatal processes--medially directed, oral projections of the paired embryonic maxillary processes--to fuse. Both gene mutations and environmental effects contribute to the complex etiology of this disorder. Although much progress has been made in identifying genes whose mutations are associated with cleft palate, little is known about the mechanisms by which the environment adversely influences gene expression during secondary palate development. An increasing body of evidence, however, implicates epigenetic processes as playing a role in adversely influencing orofacial development. Epigenetics refers to inherited changes in phenotype or gene expression caused by processes other than changes in the underlying DNA sequence. Such processes include, but are not limited to, DNA methylation, microRNA effects, and histone modifications that alter chromatin conformation. In this review, we describe our current understanding of the possible role epigenetics may play during development of the secondary palate. Specifically, we present the salient features of the embryonic palatal methylome and profile the expression of numerous microRNAs that regulate protein-encoding genes crucial to normal orofacial ontogeny.

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Nucleic acid methylation and orofacial morphogenesis

Seelan

Pisano

Greene

2019

Birth Defects Research

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In this review, we highlight the current state of knowledge of the diverse roles nucleic acid methylation plays in the embryonic development of the orofacial region and how aberrant methylation may contribute to orofacial clefts. We also consider the role of methylation in the regulation of neural crest cell function as it pertains to orofacial ontogeny. Changes in DNA methylation, as a consequence of environmental effects, have been observed in the regulatory regions of several genes, potentially identifying new candidate genes for orofacial clefting and opening promising new avenues for further research. While the focus of this review is primarily on the nonsyndromic forms of orofacial clefting, syndromic forms are briefly discussed in the context of aberrant nucleic acid methylation. K E Y W O R D Sbirth defects, epigenetics, neural crest cells, nucleic acid methylation, orofacial clefts

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Expression profiling of transforming growth factor β superfamily genes in developing orofacial tissue

Cited by 13 publications

References 113 publications

Epigenetic Regulation of Sox4 during Palate Development

Epigenetic Regulation of Sox4 during Palate Development

Developmental Epigenetics of the Murine Secondary Palate

Nucleic acid methylation and orofacial morphogenesis

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