Epigenetic Modification Factors Research Articles

Epigenetic Modification Factors and microRNAs Network Associated with Differentiation of Embryonic Stem Cells and Induced Pluripotent Stem Cells toward Cardiomyocytes: A Review.

More research is being conducted on myocardial cell treatments utilizing stem cell lines that can develop into cardiomyocytes. All of the forms of cardiac illnesses have shown to be quite amenable to treatments using embryonic (ESCs) and induced pluripotent stem cells (iPSCs). In the present study, we reviewed the differentiation of these cell types into cardiomyocytes from an epigenetic standpoint. We also provided a miRNA network that is devoted to the epigenetic commitment of stem cells toward cardiomyocyte cells and related diseases, such as congenital heart defects, comprehensively. Histone acetylation, methylation, DNA alterations, N6-methyladenosine (m6a) RNA methylation, and cardiac mitochondrial mutations are explored as potential tools for precise stem cell differentiation.

Long Non-coding RNAs Sponging MicroRNAs With Efficacy in Preclinical In Vivo Models of Esophageal Squamous Cell Cancer.

Esophageal cancer is of two subtypes: Esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC). Both are associated with a dismal prognosis. Therefore, the identification of new targets and treatment modalities is an issue of paramount importance. In this review, we focus on long non-coding RNAs (lncRNAs) which have been shown to mediate efficacy in preclinical in vivo models of ESCC by sponging microRNAs. Searching the literature, we identified four lncRNAs which were down-regulated and 23 which were up-regulated in comparison to corresponding normal tissues. The down-regulated lncRNAs lead to up-regulation of oncogenic pathways and down-regulation of tumor suppressors. The up-regulated lncRNAs target transcription factors, transmembrane receptors, cell-cycle related proteins, actin-binding proteins, signaling pathways, enzymes including epigenetic modification factors, cellular transport proteins and other categories. We describe reconstitution and inhibition of function of the corresponding lncRNAs and comment on validation and druggability of the identified targets.

KNOX II transcription factor HOS59 functions in regulating rice grain size.

Plant Knotted1-like homeobox (KNOX) genes encode homeodomain-containing transcription factors. In rice (Oryza sativa L.), little is known about the downstream target genes of KNOX Class II subfamily proteins. Here we generated chromatin immunoprecipitation (ChIP)-sequencing datasets for HOS59, a member of the rice KNOX Class II subfamily, and characterized the genome-wide binding sites of HOS59. We conducted trait ontology (TO) analysis of 9705 identified downstream target genes, and found that multiple TO terms are related to plant structure morphology and stress traits. ChIP-quantitative PCR (qPCR) was conducted to validate some key target genes. Meanwhile, our IP-MS datasets showed that HOS59 was closely associated with BELL family proteins, some grain size regulators (OsSPL13, OsSPL16, OsSPL18, SLG, etc.), and some epigenetic modification factors such as OsAGO4α and OsAGO4β, proteins involved in small interfering RNA-mediated gene silencing. Furthermore, we employed CRISPR/Cas9 editing and transgenic approaches to generate hos59 mutants and overexpression lines, respectively. Compared with wild-type plants, the hos59 mutants have longer grains and increased glume cell length, a loose plant architecture, and drooping leaves, while the overexpression lines showed smaller grain size, erect leaves, and lower plant height. The qRT-PCR results showed that mutation of the HOS59 gene led to upregulation of some grain size-related genes such as OsSPL13, OsSPL18, and PGL2. In summary, our results indicate that HOS59 may be a repressor of the downstream target genes, negatively regulating glume cell length, rice grain size, plant architecture, etc. The identified downstream target genes and possible interaction proteins of HOS59 improve our understanding of the KNOX regulatory networks.

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells.

Our studies have demonstrated that cell tumorigenicity and pluripotent differentiation potential stem from neural stemness or a neural ground state, which is defined by a regulatory network of higher levels of machineries for basic cell physiological functions, including cell cycle, ribosome biogenesis, protein translation, spliceosome, epigenetic modification factors, reprogramming factors, etc., in addition to the neural stemness specific factors. These machineries and neural stemness factors mostly play cancer-promoting roles. It can be deduced that differentiation requires the repression of neural ground state and causes the reduction or loss of neural ground state and thus tumorigenicity in tumorigenic cells. Formerly, we showed that neuronal differentiation led to reduced tumorigenicity in tumorigenic cells. In the present study, we show that non-neural pro-differentiation factors, such as GATA3, HNF4A, HHEX, and FOXA3 that specify mesodermal or/and endodermal tissues during vertebrate embryogenesis, suppress tumorigenicity via repression of neural stemness and promotion of non-neural property in tumorigenic cells. Mechanistically, these transcription factors repress the transcription of neural enriched genes and meanwhile activate genes that specify non-neural properties via direct binding to the promoters of these genes. We also show that combined expression of HHEX and FOXA3 suppresses tumorigenesis effectively in the AOM/DSS model of colitis-associated cancer. We suggest that targeting the property of neural stemness could be an effective strategy for cancer therapy.

Altered lncRNAs Transcriptomic Profiles in Atherosclerosis-Induced Ischemic Stroke.

Long non-coding RNAs (lncRNAs) can not only regulate gene transcription and translation, but also participate in the development of central nervous system diseases as epigenetic modification factors. However, their functional significance in atherosclerosis-induced ischemic stroke (AIIS) is unclear. The study aimed to screen out differentially expressed lncRNAs (delncRNAs), and to elucidate their potential regulatory mechanisms in the pathophysiology of AIIS. Based on the clinicopathological features and clinical images, we screened out 10 patients with AIIS and recruited 10 healthy volunteers. Then we used microarray to detect the whole blood RNA of subjects, and explored the biological functions of delncRNAs by GO and KEGG analysis. After further analyzing the delncRNAs of THP-1 stimulated with ox-LDL, selective lncRNAs were screened and a corresponding lncRNA-mRNA interaction network was constructed through co-expression analysis. We yielded 180 delncRNAs (44 up-regulated and 136 down-regulated) and 218 demRNAs (45 up-regulated and 173 down-regulated). Lnc-SCARNA8 and lnc-SNRPN-2 are the most significant elevated and decreased lncRNA in AIIS, respectively. The delncRNAs may play a significant role in ubiquitination-mediated protein degradation signaling pathways. According to lncRNA-mRNA network, the expression of vacuolar protein sorting 13 homolog B (VPS13B) and biliverdin reductase B (BLVRB) were significantly regulated. Our findings suggest that the ubiquitinated proteasome pathway, VPS13B and BLVRB may play a fundamental role in the pathological process of AIIS.

Updates on molecular mechanisms in the development of branched trichome in Arabidopsis and nonbranched in cotton.

SummaryTrichomes are specialized epidermal cells and a vital plant organ that protect plants from various harms and provide valuable resources for plant development and use. Some key genes related to trichomes have been identified in the model plant Arabidopsis thaliana through glabrous mutants and gene cloning, and the hub MYB‐bHLH‐WD40, consisting of several factors including GLABRA1 (GL1), GL3, TRANSPARENT TESTA GLABRA1 (TTG1), and ENHANCER OF GLABRA3 (EGL3), has been established. Subsequently, some upstream transcription factors, phytohormones and epigenetic modification factors have also been studied in depth. In cotton, a very important fibre and oil crop globally, in addition to the key MYB‐like factors, more important regulators and potential molecular mechanisms (e.g. epigenetic modifiers, distinct metabolic pathways) are being exploited during different fibre developmental stages. This occurs due to increased cotton research, resulting in the discovery of more complex regulation mechanisms from the allotetraploid genome of cotton. In addition, some conservative as well as specific mediators are involved in trichome development in other species. This study summarizes molecular mechanisms in trichome development and provides a detailed comparison of the similarities and differences between Arabidopsis and cotton, analyses the possible reasons for the discrepancy in identification of regulators, and raises future questions and foci for understanding trichome development in more detail.

GED: a manually curated comprehensive resource for epigenetic modification of gametogenesis

Reproductive infertility affects seventh of couples, which is most attributed to the obstacle of gametogenesis. Characterizing the epigenetic modification factors involved in gametogenesis is fundamental to understand the molecular mechanisms and to develop treatments for human infertility. Although the genetic factors have been implicated in gametogenesis, no dedicated bioinformatics resource for gametogenesis is available. To elucidate the relationship of epigenetic modification and mammalian gametogenesis, we developed a new database, gametogenesis epigenetic modification database (GED), a manually curated database, which aims at providing a comprehensive resource of epigenetic modification of gametogenesis. The database integrates three kinds information of epigenetic modifications during gametogenesis (DNA methylation, histone modification and RNA regulation), and the gametogenesis has been detailed as 16 stages in seven mammal species (Homo sapiens, Mus musculus, Rattus norvegicus, Sus scrofa, Bos taurus, Capra hircus and Ovis aries). Besides, we have predicted the linear pathways of epigenetic modification which were composed of 211 genes/proteins and microRNAs that were involved in gametogenesis. GED is a user-friendly Web site, through which users can obtain the comprehensive epigenetic factor information and molecular pathways by visiting our database freely. GED is free available at http://gametsepi.nwsuaflmz.com.

Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.