Epigenetic alteration of imprinted genes during neural differentiation of germline-derived pluripotent stem cells

Lee, Hye Jeong; Choi, Na Young; Lee, Seungwon; Ko, Kisung; Hwang, Tae Sook; Han, Dong Wook; Lim, Jae‐Hak; Schöler, Hans R.; Ko, Kinarm

doi:10.1080/15592294.2016.1146852

Cited by 8 publications

(10 citation statements)

References 23 publications

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“…DNA methylation status of imprinted genes may be maintained or altered during the generation of pluripotent stem cells [33]. We previously reported that the androgenetic imprinting status of H19 and Mest is maintained after reprogramming of mouse spermatogonial stem cells into germline-derived pluripotent stem cells [34]. In the present study, we confirmed that our PgHiPSCs are similar to parthenogenetic HiPSCs derived from ovarian teratoma primary fibroblasts (GM01304 and GM01306) [31].…”

Section: Discussionsupporting

confidence: 86%

Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells

et al. 2018

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Genomic imprinting is the process of epigenetic modification whereby genes are expressed in a parent-of-origin dependent manner; it plays an important role in normal growth and development. Parthenogenetic embryos contain only the maternal genome. Parthenogenetic embryonic stem cells could be useful for studying imprinted genes. In humans, mature cystic ovarian teratomas originate from parthenogenetic activation of oocytes; they are composed of highly differentiated mature tissues containing all three germ layers. To establish human parthenogenetic induced pluripotent stem cell lines (PgHiPSCs), we generated parthenogenetic fibroblasts from ovarian teratoma tissues. We compared global DNA methylation status of PgHiPSCs with that of biparental human induced pluripotent stem cells by using Illumina Infinium HumanMethylation450 BeadChip array. This analysis identified novel single imprinted CpG sites. We further tested DNA methylation patterns of two of these sites using bisulfite sequencing and described novel candidate imprinted CpG sites. These results confirm that PgHiPSCs are a powerful tool for identifying imprinted genes and investigating their roles in human development and diseases.

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Section: Discussionsupporting

confidence: 86%

Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells

et al. 2018

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“…Gene set enrichment analysis revealed significant downregulation of several biological processes in the null EBs at day 5, with multicellular organismal development (MOD) and cell surface receptor linked signal transduction (CSRLST) among the most affected ( Figure 3 B). In the MOD category, 15 of 50 genes were among the core enrichment group in the null EBs, including Pax5, Msx2, Gli1, Spry2 , and Mest , which are all important for early development or ESC differentiation ( Lee et al., 2016 , Szabo et al., 2009 , Tefft et al., 1999 , Urbanek et al., 1997 , Wu et al., 2015 ) ( Figure S4 B and Table S2 ). In the CSRLST category, 7 of 30 genes were in the core enrichment group, including Grb10 , the most downregulated gene in the null EBs ( Figure S4 C and Table S3 ).…”

Section: Resultsmentioning

confidence: 99%

GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

et al. 2018

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SummaryPrecise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF) signaling pathway in early embryoid bodies (EBs). Gcn5−/− EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation.

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“…These RNA-binding protein complexes have been detected at promoters of NANOG, SOX2 (promoter of lineage plasticity in NEPC [ 28 ]), and FGF4 [ 153 ]. H19 has also been identified in neural differentiation of pluripotent stem cells [ 154 ] but with unknown mechanisms. With such an elevated level of expression in the clinical cohorts (∼30- to 40-fold and ∼20- to 30-fold in VPC/WCM for LINC00617 and H19, respectively), these lncRNA could be responsible for maintaining the neuronal component of NEPC through epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

The long noncoding RNA landscape of neuroendocrine prostate cancer and its clinical implications

Ramnarine

Alshalalfa

et al. 2018

GigaScience

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BackgroundTreatment-induced neuroendocrine prostate cancer (tNEPC) is an aggressive variant of late-stage metastatic castrate-resistant prostate cancer that commonly arises through neuroendocrine transdifferentiation (NEtD). Treatment options are limited, ineffective, and, for most patients, result in death in less than a year. We previously developed a first-in-field patient-derived xenograft (PDX) model of NEtD. Longitudinal deep transcriptome profiling of this model enabled monitoring of dynamic transcriptional changes during NEtD and in the context of androgen deprivation. Long non-coding RNA (lncRNA) are implicated in cancer where they can control gene regulation. Until now, the expression of lncRNAs during NEtD and their clinical associations were unexplored.ResultsWe implemented a next-generation sequence analysis pipeline that can detect transcripts at low expression levels and built a genome-wide catalogue (n = 37,749) of lncRNAs. We applied this pipeline to 927 clinical samples and our high-fidelity NEtD model LTL331 and identified 821 lncRNAs in NEPC. Among these are 122 lncRNAs that robustly distinguish NEPC from prostate adenocarcinoma (AD) patient tumours. The highest expressed lncRNAs within this signature are H19, LINC00617, and SSTR5-AS1. Another 742 are associated with the NEtD process and fall into four distinct patterns of expression (NEtD lncRNA Class I, II, III, and IV) in our PDX model and clinical samples. Each class has significant (z-scores >2) and unique enrichment for transcription factor binding site (TFBS) motifs in their sequences. Enriched TFBS include (1) TP53 and BRN1 in Class I, (2) ELF5, SPIC, and HOXD1 in Class II, (3) SPDEF in Class III, (4) HSF1 and FOXA1 in Class IV, and (5) TWIST1 when merging Class III with IV. Common TFBS in all NEtD lncRNA were also identified and include E2F, REST, PAX5, PAX9, and STAF. Interrogation of the top deregulated candidates (n = 100) in radical prostatectomy adenocarcinoma samples with long-term follow-up (median 18 years) revealed significant clinicopathological associations. Specifically, we identified 25 that are associated with rapid metastasis following androgen deprivation therapy (ADT). Two of these lncRNAs (SSTR5-AS1 and LINC00514) stratified patients undergoing ADT based on patient outcome.DiscussionTo date, a comprehensive characterization of the dynamic landscape of lncRNAs during the NEtD process has not been performed. A temporal analysis of the PDX-based NEtD model has for the first time provided this dynamic landscape. TFBS analysis identified NEPC-related TF motifs present within the NEtD lncRNA sequences, suggesting functional roles for these lncRNAs in NEPC pathogenesis. Furthermore, select NEtD lncRNAs appear to be associated with metastasis and patients receiving ADT. Treatment-related metastasis is a clinical consequence of NEPC tumours. Top candidate lncRNAs FENDRR, H19, LINC00514, LINC00617, and SSTR5-AS1 identified in this study are implicated in the development of NEPC. We present here for the first time a gen...

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Epigenetic alteration of imprinted genes during neural differentiation of germline-derived pluripotent stem cells

Cited by 8 publications

References 23 publications

Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells

Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells

GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

The long noncoding RNA landscape of neuroendocrine prostate cancer and its clinical implications

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