Role of epigenetics and <scp>miRNAs</scp> in orofacial clefts

Garland, Michael A.; Sun, Bo; Zhang, Shuwen; Reynolds, Kurt; Ji, Yu; Zhou, Chengji J.

doi:10.1002/bdr2.1802

Cited by 30 publications

(13 citation statements)

References 184 publications

(215 reference statements)

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“…The etiology of CL/P is further complicated with interactions between genetic and environmental factors ( Murray, 2002 ; Beaty et al, 2016 ; Gonseth et al, 2019 ). As for environmental factors, maternal exposures to smoking and alcohol consumption are known to be a risk for CL/P ( Ericson et al, 1979 ; Munger et al, 1996 ; Romitti et al, 1999 ; Garland et al, 2020 ). In addition, several chemicals are known to be teratogens that cause CL/P [e.g., dexamethasone, dioxins, and heavy metals ( Bove et al, 1995 ; Buser and Pohl, 2015 ; Suhl et al, 2018 ; Pi et al, 2019 )].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

Yoshioka

Mikami

Ramakrishnan

et al. 2021

Front. Cell Dev. Biol.

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Cleft lip with/without cleft palate (CL/P) is one of the most common congenital birth defects, showing the complexity of both genetic and environmental contributions [e.g., maternal exposure to alcohol, cigarette, and retinoic acid (RA)] in humans. Recent studies suggest that epigenetic factors, including microRNAs (miRs), are altered by various environmental factors. In this study, to investigate whether and how miRs are involved in cleft palate (CP) induced by excessive intake of all-trans RA (atRA), we evaluated top 10 candidate miRs, which were selected through our bioinformatic analyses, in mouse embryonic palatal mesenchymal (MEPM) cells as well as in mouse embryos treated with atRA. Among them, overexpression of miR-27a-3p, miR-27b-3p, and miR-124-3p resulted in the significant reduction of cell proliferation in MEPM cells through the downregulation of CP-associated genes. Notably, we found that excessive atRA upregulated the expression of miR-124-3p, but not of miR-27a-3p and miR-27b-3p, in both in vivo and in vitro. Importantly, treatment with a specific inhibitor for miR-124-3p restored decreased cell proliferation through the normalization of target gene expression in atRA-treated MEPM cells and atRA-exposed mouse embryos, resulting in the rescue of CP in mice. Taken together, our results indicate that atRA causes CP through the induction of miR-124-3p in mice.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

Yoshioka

Mikami

Ramakrishnan

et al. 2021

Front. Cell Dev. Biol.

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“…MSX1, which we also observed at high expression in HEPM), or (iii) other types of gene regulation (e.g. miRNA 56 , 57 ). While potential TFs can be identified as presented in this study, alternative approaches also exist—for instance, integrating GWAS risk SNPs and TF databases such as JASPAR 30 .…”

Section: Discussionmentioning

confidence: 54%

Allele-specific transcription factor binding in a cellular model of orofacial clefting

Ruff

Hollstein

Fazaal

et al. 2022

Sci Rep

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Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a frequent congenital malformation with multifactorial etiology. While recent genome-wide association studies (GWAS) have identified several nsCL/P risk loci, the functional effects of the associated non-coding variants are largely unknown. Furthermore, additional risk loci remain undetected due to lack of power. As genetic variants might alter binding of transcription factors (TF), we here hypothesized that the integration of data from TF binding sites, expression analyses and nsCL/P GWAS might help to (i) identify functionally relevant variants at GWAS loci, and (ii) highlight novel risk variants that have been previously undetected. Analysing the craniofacial TF TFAP2A in human embryonic palatal mesenchyme (HEPM) cells, we identified 2845 TFAP2A ChIP-seq peaks, several of which were located near nsCL/P candidate genes (e.g. MSX1 and SPRY2). Comparison with independent data suggest that 802 of them might be specific to craniofacial development, and genes near these peaks are enriched in processes relevant to nsCL/P. Integration with nsCL/P GWAS data, however, did not show robust evidence for co-localization of common nsCL/P risk variants with TFAP2A ChIP-seq peaks. This data set represents a new resource for the analyses of craniofacial processes, and similar approaches with additional cell lines and TFs could be applied to generate further insights into nsCL/P etiology.

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“…The potential for maternal smoking to play a moderate role in CL/P etiology fits within our current understanding about the cause of CL/P being complex, multifactorial and involving both environmental and genetic factors (Dixon et al, 2011). Gene–environment interactions between smoking and CL/P have been the focus of a number of studies over the last two decades and these have improved our understanding of the pathogenesis of CL/P (Vieira, 2008; Krapels et al, 2008; Beaty et al, 2016; Garland et al, 2020). If smoking only accounts for 4% of the PAF, the environmental and genetic factors accounting for the remaining 96%, and the interplay between them, remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

Maternal Cigarette Smoking and Cleft Lip and Palate: A Systematic Review and Meta-Analysis

Fell

Dack

Chummun

et al. 2021

The Cleft Palate Craniofacial Journal

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A systematic review and meta-analysis to determine the association between active maternal smoking and cleft lip and palate etiology. Medline, Embase, Web of Science and the Cochrane Library from inception to November, 2020. Observational studies of cigarette smoking habits in pregnant women. Outcomes included cleft lip and/or palate, cleft lip ± palate and cleft palate only. Publication bias analyses were performed and the Newcastle Ottawa scales were used to assess study quality. Fixed or random effect models were used in the meta-analysis, dependent on risk of statistical heterogeneity. Forty-five studies were eligible for inclusion of which 11 were cohort and 34 were case–control studies. Sixteen studies were of sufficient standard for inclusion in the meta-analysis. The summary odds ratio for the association between smoking and cleft lip and/or palate was 1.42 (95%CI 1.27-1.59) with a population attributable fraction of 4% (95%CI 3%-5%). There was limited evidence to show a dose–response effect of smoking. This review reports a moderate association between maternal smoking and orofacial cleft but the overall quality of the conventional observational studies included was poor. There is a need for high quality and novel research strategies to further define the role of smoking in the etiology of cleft lip and palate.

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Role of epigenetics and miRNAs in orofacial clefts

Cited by 30 publications

References 184 publications

MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

Allele-specific transcription factor binding in a cellular model of orofacial clefting

Maternal Cigarette Smoking and Cleft Lip and Palate: A Systematic Review and Meta-Analysis

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