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Open AccessArticle

Meta-Analysis of Grainyhead-Like Dependent Transcriptional Networks: A Roadmap for Identifying Novel Conserved Genetic Pathways

1
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora 3086, VIC, Australia
2
School of Biological Sciences, Monash University, Clayton 3168, VIC, Australia
3
Australian Craniofacial Unit, Women and Children’s Hospital, Adelaide 5005, SA, Australia
4
Faculty of Health Sciences, University of Adelaide, Adelaide 5005, SA, Australia
5
Nanjing Medical University, Nanjing 210029, China
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Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland
7
Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Rd., Melbourne 3004, VIC, Australia
8
Department of Pharmacy and Biomedical Sciences, La Trobe University, Bendigo 3552, VIC, Australia
9
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St.02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(11), 876; https://doi.org/10.3390/genes10110876
Received: 3 October 2019 / Revised: 25 October 2019 / Accepted: 28 October 2019 / Published: 31 October 2019
(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)
The Drosophila grainyhead (grh) and vertebrate Grainyhead-like (Grhl) transcription factors are among the most critical genes for epithelial development, maintenance and homeostasis, and are remarkably well conserved from fungi to humans. Mutations affecting grh/Grhl function lead to a myriad of developmental and adult onset epithelial disease, such as aberrant skin barrier formation, facial/palatal clefting, impaired neural tube closure, age-related hearing loss, ectodermal dysplasia, and importantly, cancers of epithelial origin. Recently, mutations in the family member GRHL3 have been shown to lead to both syndromic and non-syndromic facial and palatal clefting in humans, particularly the genetic disorder Van Der Woude Syndrome (VWS), as well as spina bifida, whereas mutations in mammalian Grhl2 lead to exencephaly and facial clefting. As transcription factors, Grhl proteins bind to and activate (or repress) a substantial number of target genes that regulate and drive a cascade of transcriptional networks. A multitude of large-scale datasets have been generated to explore the grh/Grhl-dependent transcriptome, following ablation or mis-regulation of grh/Grhl-function. Here, we have performed a meta-analysis of all 41 currently published grh and Grhl RNA-SEQ, and microarray datasets, in order to identify and characterise the transcriptional networks controlled by grh/Grhl genes across disparate biological contexts. Moreover, we have also cross-referenced our results with published ChIP and ChIP-SEQ datasets, in order to determine which of the critical effector genes are likely to be direct grh/Grhl targets, based on genomic occupancy by grh/Grhl genes. Lastly, to interrogate the predictive strength of our approach, we experimentally validated the expression of the top 10 candidate grhl target genes in epithelial development, in a zebrafish model lacking grhl3, and found that orthologues of seven of these (cldn23, ppl, prom2, ocln, slc6a19, aldh1a3, and sod3) were significantly down-regulated at 48 hours post-fertilisation. Therefore, our study provides a strong predictive resource for the identification of putative grh/grhl effector target genes. View Full-Text
Keywords: Grainyhead; Grhl; epithelia; cleft palate; craniofacial; meta-analysis Grainyhead; Grhl; epithelia; cleft palate; craniofacial; meta-analysis
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Mathiyalagan, N.; Miles, L.B.; Anderson, P.J.; Wilanowski, T.; Grills, B.L.; McDonald, S.J.; Keightley, M.C.; Charzynska, A.; Dabrowski, M.; Dworkin, S. Meta-Analysis of Grainyhead-Like Dependent Transcriptional Networks: A Roadmap for Identifying Novel Conserved Genetic Pathways. Genes 2019, 10, 876.

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