Tissue-specific and imprinted epigenetic modifications of the human NDN gene

Lau, Jason C. Y.; Hanel, Meredith L.; Wevrick, Rachel

doi:10.1093/nar/gkh671

Cited by 49 publications

(44 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we identified necdin to be upstream of Wnt, how other preadipocyte-selective or anti-adipogenic genes regulate necdin expression in HSCs, is unknown at the present time. Of equal importance is epigenetic regulation of necdin via paternal allelespecific histone acetylation, which appears to contribute to tissue-specific activity (36). In summary, our study has identified necdin as a new regulator for the cell fate of HSCs.…”

mentioning

confidence: 71%

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Zhu

Wang

Tsukamoto

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hepatic stellate cells (HSCs), vitamin A-storing liver pericytes, undergo myofibroblastic trans-differentiation or "activation" to participate in liver wound healing. This cellular process involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor ␥ (PPAR␥). Necdin, a melanoma antigen family protein, promotes neuronal and myogenic differentiation while inhibiting adipogenesis. The present study demonstrates that necdin is selectively expressed in HSCs among different liver cell types and induced during their activation in vitro and in vivo. Silencing of necdin with adenovirally expressed shRNA, reverses activated HSCs to quiescent cells in a manner dependent on PPAR␥ and suppressed canonical Wnt signaling. Promoter analysis, site-directed mutagenesis, and chromatin immunoprecipitation demonstrate that Wnt10b, a canonical Wnt induced in activated HSCs, is a direct target of necdin. Necdin silencing abrogates three epigenetic signatures implicated in repression of PPAR␥: increased MeCP2 (methyl CpG binding protein 2) and HP-1␣ co-repressor recruitments to Ppar␥ promoter and enhanced H3K27 dimethylation at the exon 5 locus, again in a manner dependent on suppressed canonical Wnt. These epigenetic effects are reproduced by antagonism of canonical Wnt signaling with Dikkopf-1. Our results demonstrate a novel necdinWnt pathway, which serves to mediate antiadipogenic HSC trans-differentiation via epigenetic repression of PPAR␥. Hepatic stellate cells (HSCs)2 are desmin-positive mesenchymal cells located in the subendothelial (perisinusoidal) space of hepatic sinusoids. They store vitamin A, function as hepatic pericytes, communicate with hepatocytes via a gap junction and the release of soluble factors, and produce the components of the normal matrix milieu of the perisinusoidal space. HSCs also actively participate in matrix remodeling and wound healing through their production of matrix metalloproteinases and extracellular matrix proteins and are considered as one of the principal cell types responsible for the genesis of liver fibrosis (1). The most unique feature of the manner in which HSCs participate in liver fibrogenesis is their myofibroblastic transdifferentiation (activation) characterized by depletion of vitamin A storage, cell proliferation, induction of matrix genes, and acquisition of the myofibroblastic phenotype via induction of ␣-smooth muscle actin. Although major classes of mediators are identified for HSC trans-differentiation, including soluble factors (cytokines, hormones, and lipid mediators), reactive oxygen species, and altered extracellular matrix milieu (1), the fundamental understanding of cell lineage and cell fate regulation of HSCs is elusive. In this regard, Asahina et al. (2) has demonstrated recently the mesenchymal origin of fetal HSCs and "submesothelial cell" as a potential precursor for HSCs. Intriguingly, HSCs express markers for cell types derived from multipotent mesenchymal progenitor cells such as neural cells, chondrocyt...

show abstract

mentioning

confidence: 71%

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Zhu

Wang

Tsukamoto

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To study how PWS-IC activates the genes on the paternal allele across the PWS/AS domain, we chose NDN as a representative gene, which is monoallelically expressed mainly in brain (11), being simple, intronless, and a member of the upstream PEG cluster, which includes NDN, MKRN3, and MAGEL2, and is believed to be a target of the PWS-IC activating function (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…To discriminate between the maternal and paternal alleles, we used lymphoblasts from a Prader-Willi patient and his father, who carried a deletion in their PWS-IC on one chromosome (PWS-U family) and from an Angelman patient and his mother, who were deleted in AS-IC (AS-D family). Although NDN is not expressed in these lymphoblasts, it is differentially methylated (11). Chromatin of these lymphoblast cells was subjected to the 3c procedure (SI Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains

Rabinovitz¹,

Kaufman²,

Ludwig³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted domain is regulated by a bipartite imprinting control center (IC) composed of a sequence around the SNRPN promoter (PWS-IC) and a 880-bp sequence located 35 kb upstream (AS-IC). The AS-IC imprint is established during gametogenesis and confers repression upon PWS-IC on the maternal allele. Mutation at PWS-IC on the paternal allele leads to gene silencing across the entire PWS/AS domain. This silencing implies that PWS-IC functions on the paternal allele as a bidirectional activator. Here we examine the mechanism by which PWS-IC activates the paternally expressed genes (PEGs) using transgenes that include the PWS-IC sequence in the presence or absence of AS-IC and NDN, an upstream PEG, as an experimental model. We demonstrate that PWS-IC is in fact an activator of NDN. This activation requires an unmethylated PWS-IC in the gametes and during early embryogenesis. PWS-IC is dispensable later in development. Interestingly, a similar activation of a nonimprinted gene (APOA1) was observed, implying that PWS-IC is a universal activator. To decipher the mechanism by which PWS-IC confers activation of remote genes, we performed methylated DNA immunoprecipitation (MeDIP) array analysis on lymphoblast cell lines that revealed dispersed, rather than continued differential methylation. However, chromatin conformation capture (3c) experiments revealed a physical interaction between PWS-IC and the PEGs, suggesting that activation of PEGs may require their proximity to PWS-IC.

show abstract

“…We established 11 assays based on literature review [22][23][24][25][26][27][28][29] , as shown in Supplementary Table S2. We failed to establish a reliable bisulphite pyrosequencing assay for the KvDMR/IC2 in 11p15.…”

Section: Bisulphite Pyrosequencingmentioning

confidence: 99%

Frequency and characterization of DNA methylation defects in children born SGA

et al. 2012

View full text Add to dashboard Cite

Various genes located at imprinted loci and regulated by epigenetic mechanisms are involved in the control of growth and differentiation. The broad phenotypic variability of imprinting disorders suggests that individuals with inborn errors of imprinting might remain undetected among patients born small for gestational age (SGA). We evaluated quantitative DNA methylation analysis at differentially methylated regions (DMRs) of 10 imprinted loci (PLAGL1, IGF2R DMR2, GRB10, H19 DMR, IGF2, MEG3, NDN, SNRPN, NESP, NESPAS) by bisulphite pyrosequencing in 98 patients born SGA and 50 controls. For IGF2R DMR2, methylation patterns of additional 47 parent pairs and one mother (95 individuals) of patients included in the SGA cohort were analyzed. In six out of 98 patients born SGA, we detected DNA methylation changes at single loci. In one child, the diagnosis of upd(14)mat syndrome owing to an epimutation of the MEG3 locus in 14q32 could be established. The remaining five patients showed hypomethylation at GRB10 (n ¼ 2), hypomethylation at the H19 3CTCF-binding site (n ¼ 1), hypermethylation at NDN (n ¼ 1) and hypermethylation at IGF2 (n ¼ 1). IGF2R DMR2 hypermethylation was detected in five patients, six parents of patients in the SGA cohort and two controls. We conclude that aberrant methylation at imprinted loci in children born SGA exists but seems to be rare if known imprinting syndromes are excluded. Further investigations on the physiological variations and the functional consequences of the detected aberrant methylation are necessary before final conclusions on the clinical impact can be drawn.

show abstract

Tissue-specific and imprinted epigenetic modifications of the human NDN gene

Cited by 49 publications

References 49 publications

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains

Frequency and characterization of DNA methylation defects in children born SGA

Contact Info

Product

Resources

About