'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Thu, 21 Jan 2021 10:33:06 EST Thu, 21 Jan 2021 10:33:06 EST jirtle@radonc.duke.edu james001@jirtle.com CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice. Schmid RS, Deng X, Panikker P, Msackyi M, Breton C, Wilson JM
J Clin Invest (Jan 2021)

Gene editing holds the potential to correct mutations and cure devastating genetic disorders. The technology has not yet proven efficacious for therapeutic use in central nervous system (CNS) diseases with ubiquitous neuronal defects. Angelman syndrome (AS), a severe neurodevelopmental disorder, is caused by a lack of maternal expression of the UBE3A gene. Due to genomic imprinting, only neurons are affected. One therapeutic approach focuses on the intact paternal UBE3A copy in AS patients that is silenced by an antisense transcript (UBE3A-ATS). We show here that gene editing of Ube3a-ATS in the mouse brain results in the formation of base pair insertions/deletions (indels) in neurons and the subsequent unsilencing of the paternal Ube3a allele in neurons, which partially corrects the behavior phenotype of a murine AS model. This study provides compelling evidence to further investigate editing of the homologous region of the human UBE3A-ATS, since this may provide a lasting therapeutic effect for AS patients.]]> Wed, 31 Dec 1969 19:00:00 EST Aging Atlas: a multi-omics database for aging biology.  
Nucleic Acids Res (01 2021)

Organismal aging is driven by interconnected molecular changes encompassing internal and extracellular factors. Combinational analysis of high-throughput 'multi-omics' datasets (gathering information from genomics, epigenomics, transcriptomics, proteomics, metabolomics and pharmacogenomics), at either populational or single-cell levels, can provide a multi-dimensional, integrated profile of the heterogeneous aging process with unprecedented throughput and detail. These new strategies allow for the exploration of the molecular profile and regulatory status of gene expression during aging, and in turn, facilitate the development of new aging interventions. With a continually growing volume of valuable aging-related data, it is necessary to establish an open and integrated database to support a wide spectrum of aging research. The Aging Atlas database aims to provide a wide range of life science researchers with valuable resources that allow access to a large-scale of gene expression and regulation datasets created by various high-throughput omics technologies. The current implementation includes five modules: transcriptomics (RNA-seq), single-cell transcriptomics (scRNA-seq), epigenomics (ChIP-seq), proteomics (protein-protein interaction), and pharmacogenomics (geroprotective compounds). Aging Atlas provides user-friendly functionalities to explore age-related changes in gene expression, as well as raw data download services. Aging Atlas is freely available at https://bigd.big.ac.cn/aging/index.]]> Wed, 31 Dec 1969 19:00:00 EST Technical advancements in epigenomics and applications in transplantation. Kuscu C, Eason JD, Kuscu C
Curr Opin Organ Transplant (Feb 2021)

To summarize recently developed next generation sequencing-based methods to study epigenomics and epitranscriptomics. To elucidate the potential applications of these recently developed methods in transplantation research.]]> Wed, 31 Dec 1969 19:00:00 EST Applications of Omics Technologies for 3D In Vitro Disease Models. Pieters V, Co I, Wu N, McGuigan AP
Tissue Eng Part C Methods (Jan 2021)

Omics technologies, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, multi-omics, and integrated modalities, have greatly contributed to our understanding of various diseases by enabling researchers to probe the molecular wiring of cellular systems in a high-content and precise manner. With the development of tissue engineered 3D in vitro disease models, such as organoids and spheroids, there is potential of integrating omics technologies with 3D disease models to elucidate the complex links between genotype and phenotype. These 3D disease models have been used to model cancer, infectious disease, toxicity, neurological disorders and others. In this review, we provide an overview of omics technologies, highlight current and emerging studies in the context of in vitro disease models, discuss the associated experimental design considerations, barriers and challenges of omics technologies, and provide an outlook on the future applications of omics technologies with 3D models. Overall, this review aims to provide a valuable resource for tissue engineers seeking to leverage omics technologies for diving deeper into biological discovery.]]> Wed, 31 Dec 1969 19:00:00 EST Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects. Takei R, Cadzow M, Markie D, Bixley M, Phipps-Green A, Major TJ, Li C, Choi HK, Li Z, Hu H,  , Guo H, He M, Shi Y, Stamp LK, Dalbeth N, Merriman TR, Wei WH
J Hum Genet (Feb 2021)

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.]]> Wed, 31 Dec 1969 19:00:00 EST Accelerated Epigenetic Age in Normal Cognitive Aging of Korean Community-Dwelling Older Adults. Park J, Won CW, Saligan LN, Kim YJ, Kim Y, Lukkahatai N
Biol Res Nurs (Jan 2021)

Epigenetic age acceleration has been studied as a promising biomarker of age-related conditions, including cognitive aging. This pilot study aims to explore potential cognitive aging-related biomarkers by investigating the relationship of epigenetic age acceleration and cognitive function and by examining the epigenetic age acceleration differences between successful cognitive aging (SCA) and normal cognitive aging (NCA) among Korean community-dwelling older adults (CDOAs).]]> Wed, 31 Dec 1969 19:00:00 EST Insights into glucocorticoid responses derived from omics studies. Kan M, Himes BE
Pharmacol Ther (Feb 2021)

Glucocorticoid drugs are commonly used in the treatment of several conditions, including autoimmune diseases, asthma and cancer. Despite their widespread use and knowledge of biological pathways via which they act, much remains to be learned about the cell type-specific mechanisms of glucocorticoid action and the reasons why patients respond differently to them. In recent years, human and in vitro studies have addressed these questions with genomics, transcriptomics and other omics approaches. Here, we summarize key insights derived from omics studies of glucocorticoid response, and we identify existing knowledge gaps related to mechanisms of glucocorticoid action that future studies can address.]]> Wed, 31 Dec 1969 19:00:00 EST Cell-specific characterization of the placental methylome. Yuan V, Hui D, Yin Y, Peñaherrera MS, Beristain AG, Robinson WP
BMC Genomics (Jan 2021)

DNA methylation (DNAm) profiling has emerged as a powerful tool for characterizing the placental methylome. However, previous studies have focused primarily on whole placental tissue, which is a mixture of epigenetically distinct cell populations. Here, we present the first methylome-wide analysis of first trimester (n = 9) and term (n = 19) human placental samples of four cell populations: trophoblasts, Hofbauer cells, endothelial cells, and stromal cells, using the Illumina EPIC methylation array, which quantifies DNAm at > 850,000 CpGs.]]> Wed, 31 Dec 1969 19:00:00 EST Relative mRNA and protein stability of epigenetic regulators in musculoskeletal cell culture models. Badreldin AA, Bagheri L, Zhang B, Larson AN, van Wijnen AJ
Gene (Jan 2021)

Control of gene expression by epigenetic regulators is fundamental to tissue development and homeostasis. Loss-of-function (LOF) studies using siRNAs for epigenetic regulators require that RNA interference rapidly reduces the cellular levels of the corresponding mRNAs and/or proteins. The most abundant chromatin structural proteins (i.e., the core histones H2A, H2B, H3 and H4) have relatively long half-lives and do not turn over rapidly, although their mRNAs are labile. The question arises whether epigenetic regulatory enzymes (e.g., Ezh2) or proteins that interact with histones via selective modifications (e.g., Cbx1 to Cbx8, Brd4) are stable or unstable. Therefore, we performed classical α-amanitin and cycloheximide inhibition assays that block, respectively, mRNA transcription and protein translation in mouse MC3T3 osteoblasts, ATDC5 chondrocytes and C2C12 myoblasts. We find that mRNA levels of Cbx proteins and Ezh2 were significantly depleted after 24 hrs, while their corresponding proteins remained relatively stable. As positive control, the half-life of the labile cyclin D1 protein was found to be less than 1 hr. Our study suggests that histone code readers and writers are relatively stable chromatin-related proteins, which is consistent with their long-term activities in maintaining chromatin organization and phenotype identity. These findings have conceptual ramifications for the interpretation of RNAi experiments that reduce the mRNA but not protein levels of epiregulatory proteins. We propose that siRNAs for at least some epigenetic regulatory proteins may exert their biological effects by blocking translation and new protein synthesis rather than by decreasing pre-existing protein pools.]]> Wed, 31 Dec 1969 19:00:00 EST Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): Opportunities for personalized therapies. Arakelyan J, Zohrabyan D, Philip PA
Cancer (Feb 2021)

Pancreatic neuroendocrine neoplasms (panNENs) are the second most common epithelial tumors of the pancreas. Despite improvements in prognostic grading and staging systems, it remains a challenge to predict the clinical behavior of panNENs and the response to specific therapies given the high degree of heterogeneity of these tumors. Most panNENs are nonfunctional and present as advanced disease. However, systemic therapies provide modest benefits. Therefore, there is a need for predictive biomarkers to develop personalized treatment and to advance new drug development. The somatostatin receptors remain the only clinically established prognostic and predictive biomarkers in panNENs. Oncogenic drivers are at a very low frequency. Commonly mutated genes in panNENs include MEN1, chromatin remodeling genes (DAXX and ATRX), and mammalian target of rapamycin pathway genes. In contrast, poorly differentiated neuroendocrine carcinomas (panNECs), which carry a very poor prognosis, have distinctive mutations in certain genes (eg, RB1 and p53). Ongoing research to integrate epigenomics will provide tremendous opportunities to improve current understanding of the clinical heterogeneity of pancreatic neuroendocrine tumors and provide invaluable insight into the biology of these tumors, new drug development, and establishing personalized therapies.]]> Wed, 31 Dec 1969 19:00:00 EST Polymer modelling unveils the roles of heterochromatin and nucleolar organizing regions in shaping 3D genome organization in Arabidopsis thaliana. Di Stefano M, Nützmann HW, Marti-Renom MA, Jost D
Nucleic Acids Res (Jan 2021)

The 3D genome is characterized by a complex organization made of genomic and epigenomic layers with profound implications on gene regulation and cell function. However, the understanding of the fundamental mechanisms driving the crosstalk between nuclear architecture and (epi)genomic information is still lacking. The plant Arabidopsis thaliana is a powerful model organism to address these questions owing to its compact genome for which we have a rich collection of microscopy, chromosome conformation capture (Hi-C) and ChIP-seq experiments. Using polymer modelling, we investigate the roles of nucleolus formation and epigenomics-driven interactions in shaping the 3D genome of A. thaliana. By validation of several predictions with published data, we demonstrate that self-attracting nucleolar organizing regions and repulsive constitutive heterochromatin are major mechanisms to regulate the organization of chromosomes. Simulations also suggest that interphase chromosomes maintain a partial structural memory of the V-shapes, typical of (sub)metacentric chromosomes in anaphase. Additionally, self-attraction between facultative heterochromatin regions facilitates the formation of Polycomb bodies hosting H3K27me3-enriched gene-clusters. Since nucleolus and heterochromatin are highly-conserved in eukaryotic cells, our findings pave the way for a comprehensive characterization of the generic principles that are likely to shape and regulate the 3D genome in many species.]]> Wed, 31 Dec 1969 19:00:00 EST DNA sequences performs as natural language processing by exploiting deep learning algorithm for the identification of N4-methylcytosine. Wahab A, Tayara H, Xuan Z, Chong KT
Sci Rep (Jan 2021)

N4-methylcytosine is a biochemical alteration of DNA that affects the genetic operations without modifying the DNA nucleotides such as gene expression, genomic imprinting, chromosome stability, and the development of the cell. In the proposed work, a computational model, 4mCNLP-Deep, used the word embedding approach as a vector formulation by exploiting deep learning based CNN algorithm to predict 4mC and non-4mC sites on the C.elegans genome dataset. Diversity of ranges employed for the experimental such as corpus k-mer and k-fold cross-validation to obtain the prevailing capabilities. The 4mCNLP-Deep outperform from the state-of-the-art predictor by achieving the results in five evaluation metrics by following; Accuracy (ACC) as 0.9354, Mathew's correlation coefficient (MCC) as 0.8608, Specificity (Sp) as 0.89.96, Sensitivity (Sn) as 0.9563, and Area under curve (AUC) as 0.9731 by using 3-mer corpus word2vec and 3-fold cross-validation and attained the increment of 1.1%, 0.6%, 0.58%, 0.77%, and 4.89%, respectively. At last, we developed the online webserver http://nsclbio.jbnu.ac.kr/tools/4mCNLP-Deep/ , for the experimental researchers to get the results easily.]]> Wed, 31 Dec 1969 19:00:00 EST Genomics and Epigenomics of Pituitary Tumors: What Do Pathologists Need to Know? Asa SL, Mete O, Ezzat S
Endocr Pathol (Jan 2021)

Molecular pathology has advanced our understanding of many tumors and offers opportunities to identify novel therapies. In the pituitary, the field has uncovered several genetic mutations that predispose to pituitary neuroendocrine tumor (PitNET) development, including MEN1, CDKN1B, PRKRIα, AIP, GPR101, and other more rare events; however, these genes are only rarely mutated in sporadic PitNETs. Recurrent genetic events in sporadic PitNETs include GNAS mutations in a subset of somatotroph tumors and ubiquitin-specific peptidase mutations (e.g., USP8, USP48) in some corticotroph tumors; to date, neither of these has resulted in altered management, and instead, the prognosis and management of PitNETs still rely more on cell type and subtype as well as local growth that determines surgical resectability. In contrast, craniopharyngiomas have either CTNNB1 or BRAF mutations that correlate with adamantinomatous or papillary morphology, respectively; the latter offers the opportunity for targeted therapy. DICER1 mutations are found in patients with pituitary blastoma. Epigenetic changes are implicated in the pathogenesis of the more common sporadic pituitary neoplasms including the majority of PitNETs and tumors of pituicytes.]]> Wed, 31 Dec 1969 19:00:00 EST Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation. Aslam MA, Alemdehy MF, Kwesi-Maliepaard EM, Muhaimin FI, Caganova M, Pardieck IN, van den Brand T, van Welsem T, de Rink I, Song JY, de Wit E, Arens R, Jacobs H, van Leeuwen F
EMBO Rep (Jan 2021)

Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation.]]> Wed, 31 Dec 1969 19:00:00 EST Regulation of the epigenetic landscape by immune cell oxidants. Das AB, Seddon AR, O'Connor KM, Hampton MB
Free Radic Biol Med (Jan 2021)

Excessive production of microbicidal oxidants by neutrophils can damage host tissue. The short-term response of cells to oxidative stress is well understood, but the mechanisms behind long-term consequences require further clarification. Epigenetic pathways mediate cellular adaptation, and are therefore a potential target of oxidative stress. Indeed, there is evidence that many proteins and metabolites involved in epigenetic pathways are redox sensitive. In this review we provide an overview of the epigenetic landscape and discuss the potential for redox regulation. Using this information, we highlight specific examples where neutrophil oxidants react with epigenetic pathway components. We also use published data from redox proteomics to map out known intersections between oxidative stress and epigenetics that may signpost helpful directions for future investigation. Finally, we discuss the role neutrophils play in adaptive pathologies with a focus on tumour initiation and progression. We hope this information will stimulate further discourse on the emerging field of redox epigenomics.]]> Wed, 31 Dec 1969 19:00:00 EST Integrative analysis of epigenomics, transcriptomics, and proteomics to identify key targets and pathways of Weining granule for gastric cancer. Liang MK, Liang XQ, Zhong J, Wei YT, Lian ZP, Huang ZK, Liang J
J Ethnopharmacol (Jan 2021)

Weining granule (WNG) is a "Qi-Enriching and Kidney-Tonifying, Spleen-Reinforcing and Stasis-Removing" formula for gastric cancer (GC). Past research we noted WNG inhibited cell growth and raised apoptosis in GC. However, the underlying mechanism of WNG for GC have yet to be systematically clarified.]]> Wed, 31 Dec 1969 19:00:00 EST Genetic Dissection of a Super Enhancer Controlling the Cluster in the Heart. Man JCK, van Duijvenboden K, Krijger PHL, Hooijkaas IB, van der Made I, de Gier-de Vries C, Wakker V, Creemers EE, de Laat W, Boukens BJ, Christoffels VM
Circ Res (Jan 2021)

ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide), encoded by the clustered genes and , are important prognostic, diagnostic, and therapeutic proteins in cardiac disease. The spatiotemporal expression pattern and stress-induction of the and are tightly regulated, possibly involving their coregulation by an evolutionary conserved enhancer cluster.]]> Wed, 31 Dec 1969 19:00:00 EST Chromatin Manipulation and Editing: Challenges, New Technologies and Their Use in Plants. Fal K, Tomkova D, Vachon G, Chabouté ME, Berr A, Carles CC
Int J Mol Sci (Jan 2021)

An ongoing challenge in functional epigenomics is to develop tools for precise manipulation of epigenetic marks. These tools would allow moving from correlation-based to causal-based findings, a necessary step to reach conclusions on mechanistic principles. In this review, we describe and discuss the advantages and limits of tools and technologies developed to impact epigenetic marks, and which could be employed to study their direct effect on nuclear and chromatin structure, on transcription, and their further genuine role in plant cell fate and development. On one hand, epigenome-wide approaches include drug inhibitors for chromatin modifiers or readers, nanobodies against histone marks or lines expressing modified histones or mutant chromatin effectors. On the other hand, locus-specific approaches consist in targeting precise regions on the chromatin, with engineered proteins able to modify epigenetic marks. Early systems use effectors in fusion with protein domains that recognize a specific DNA sequence (Zinc Finger or TALEs), while the more recent dCas9 approach operates through RNA-DNA interaction, thereby providing more flexibility and modularity for tool designs. Current developments of "second generation", chimeric dCas9 systems, aiming at better targeting efficiency and modifier capacity have recently been tested in plants and provided promising results. Finally, recent proof-of-concept studies forecast even finer tools, such as inducible/switchable systems, that will allow temporal analyses of the molecular events that follow a change in a specific chromatin mark.]]> Wed, 31 Dec 1969 19:00:00 EST 3DIV update for 2021: a comprehensive resource of 3D genome and 3D cancer genome. Kim K, Jang I, Kim M, Choi J, Kim MS, Lee B, Jung I
Nucleic Acids Res (01 2021)

Three-dimensional (3D) genome organization is tightly coupled with gene regulation in various biological processes and diseases. In cancer, various types of large-scale genomic rearrangements can disrupt the 3D genome, leading to oncogenic gene expression. However, unraveling the pathogenicity of the 3D cancer genome remains a challenge since closer examinations have been greatly limited due to the lack of appropriate tools specialized for disorganized higher-order chromatin structure. Here, we updated a 3D-genome Interaction Viewer and database named 3DIV by uniformly processing ∼230 billion raw Hi-C reads to expand our contents to the 3D cancer genome. The updates of 3DIV are listed as follows: (i) the collection of 401 samples including 220 cancer cell line/tumor Hi-C data, 153 normal cell line/tissue Hi-C data, and 28 promoter capture Hi-C data, (ii) the live interactive manipulation of the 3D cancer genome to simulate the impact of structural variations and (iii) the reconstruction of Hi-C contact maps by user-defined chromosome order to investigate the 3D genome of the complex genomic rearrangement. In summary, the updated 3DIV will be the most comprehensive resource to explore the gene regulatory effects of both the normal and cancer 3D genome. '3DIV' is freely available at http://3div.kr.]]> Wed, 31 Dec 1969 19:00:00 EST Comparative genome-wide DNA methylation analysis in myocardial tissue from donors with and without Down syndrome. Cejas RB, Wang J, Hageman-Blair R, Liu S, Blanco JG
Gene (Jan 2021)

Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors' age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.]]> Wed, 31 Dec 1969 19:00:00 EST