Abnormal epigenetic regulation of the gene expression levels of Wnt2b and Wnt7b: Implications for neural tube defects

Bai, Baoling; Chen, Shuyuan; Zhang, Qin; Jiang, Qian; Li, Huili

doi:10.3892/mmr.2015.4514

Cited by 12 publications

(13 citation statements)

References 24 publications

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“…Results from recent studies show that not only gene mutations but also aberrant gene expression are important in NTDs [27]. Previous work from our laboratory has confirmed that abnormal expression of Wnt2b and Wnt7b is involved in human NTDs [28]. In this study, we attempted to explore the role of abnormal expression of HOX genes in NTDs as well as its underlining regulatory mechanism, based our data from transcriptome profile analysis of RA-induced mouse NTDs embryos.…”

Section: Discussionmentioning

confidence: 99%

Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects

Wang

Pei

et al. 2019

Epigenetics & Chromatin

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BackgroundNeural tube defects (NTDs) are severe, common birth defects that result from failure of normal neural tube closure during early embryogenesis. Accumulating strong evidence indicates that genetic factors contribute to NTDs etiology, among them, HOX genes play a key role in neural tube closure. Although abnormal HOX gene expression can lead to NTDs, the underlying pathological mechanisms have not fully been understood.MethodWe detected that H3K27me3 and expression of the Hox genes in a retinoic acid (RA) induced mouse NTDs model on E8.5, E9.5 and E10.5 using RNA-sequencing and chromatin immunoprecipitation sequencing assays. Furthermore, we quantified 10 Hox genes using NanoString nCounter in brain tissue of fetuses with 39 NTDs patients including anencephaly, spina bifida, hydrocephaly and encephalocele.ResultsHere, our results showed differential expression in 26 genes with a > 20-fold change in the level of expression, including 10 upregulated Hox genes. RT-qPCR revealed that these 10 Hox genes were all upregulated in RA-induced mouse NTDs as well as RA-treated embryonic stem cells (ESCs). Using ChIP-seq assays, we demonstrate that a decrease in H3K27me3 level upregulates the expression of Hox cluster A–D in RA-induced mouse NTDs model on E10.5. Interestingly, RA treatment led to attenuation of H3K27me3 due to cooperate between UTX and Suz12, affecting Hox gene regulation. Further analysis, in human anencephaly cases, upregulation of 10 HOX genes was observed, along with aberrant levels of H3K27me3. Notably, HOXB4, HOXC4 and HOXD1 expression was negatively correlated with H3K27me3 levels.ConclusionOur results indicate that abnormal HOX gene expression induced by aberrant H3K27me3 levels may be a risk factor for NTDs and highlight the need for further analysis of genome-wide epigenetic modification in NTDs.

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Section: Discussionmentioning

confidence: 99%

Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects

Wang

Pei

et al. 2019

Epigenetics & Chromatin

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“…Both genetic and epigenetic factors have been studied to identify the etiology of NTDs, especially since folate deficiency has been indicated as a cofactor of NTD occurrence [34]. Recent studies suggested that histone modifications such as acetylation or methylation correlated with the occurrence of NTD in mouse or chick embryos [35][36][37][38][39]. Further, chromatin modifications have been linked to defective neurogenesis and patterning of the embryonic spinal cord [40][41][42].…”

Section: Introductionmentioning

confidence: 99%

Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression

et al. 2020

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Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2.

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“…WNT3a deficiency causes irrevocable damage to the hematopoietic stem cell's self renewal, resulting in defects in progenitor cell differentiation [12]. WNT7b can act both canonically and non-canonically by involving in convergent extension movement and increase in signaling, thus possibly leading to distorted neural development [13]. Proteinprotein interactions (PPIs) are important for cell-cell communication, signaling pathways and several other biological processes and main goal behind these PPIs is to find out specific function of specific protein [14].…”

Section: Introductionmentioning

confidence: 99%

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2020

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WNT proteins are involved from initial of neural tissue specification to the end of cell fate determination and organ development. The present work was carried out to understand the involvement of different WNT isoforms (WNT3a, WNT5a and WNT7b) in neural development. A total of 718, 546 and 1004 PPIs for WNT3a, WNT5a and WNT7b respectively, were predicted by STRING database with confidence score more than 0.400. A network carrying all the selected PPIs of targeted proteins was constructed by using Cytoscape by assigning source node, target node and combined score as edge attribute. A total 2268 interactions of WNT3a, WNT5a and WNT7b were predicted to be involved in multiple signaling pathways and developmental processes. 43 of 2268 PPIs were refined after analyzing role of targeted proteins specifically in brain and neural development. WNT3a, WNT5a and WNT7a were predicted to be interacting with 18, 17 and 11 proteins, respectively, with average node degree score of 1.89, 2.12 and 1.82 respectively. The CytoHubba algorithm identified WNT3a, WNT5a, and WNT7b as hub proteins in neural development ranked on the basis of EPC (Edge Percolated Component) score of 9.352, 9.258 and 8.387.

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Abnormal epigenetic regulation of the gene expression levels of Wnt2b and Wnt7b: Implications for neural tube defects

Cited by 12 publications

References 24 publications

Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects

Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects

Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression

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