'; ?> 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 Mon, 17 Jan 2022 07:24:29 EST Mon, 17 Jan 2022 07:24:29 EST jirtle@radonc.duke.edu james001@jirtle.com Endometrial Cancer Characteristics and Risk of Recurrence. Borden LE, Locklear TM, Grider DJ, Osborne JL, Saks EJ, Valea FA, Iglesias DA
Am J Clin Pathol (Jan 2022)

To describe clinicopathologic characteristics and survival outcomes of endometrial adenocarcinomas stratified by mismatch repair (MMR) status.]]>
Wed, 31 Dec 1969 19:00:00 EST
Computational modeling of chromatin accessibility identified important epigenomic regulators. Zhao Y, Dong Y, Hong W, Jiang C, Yao K, Cheng C
BMC Genomics (Jan 2022)

Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.]]>
Wed, 31 Dec 1969 19:00:00 EST
Understanding the role of telomere attrition and epigenetic signatures in COVID-19 severity. Mahmoodpoor A, Sanaie S, Roudbari F, Sabzevari T, Sohrabifar N, Kazeminasab S
Gene (Feb 2022)

Within the past several decades, the emergence and spread of infectious diseases with pandemic potential have endangered human lives. Coronavirus disease 2019 (COVID-19) outbreak represents an unprecedented threat for all health systems worldwide. The clinical spectrum of COVID-19 is highly heterogeneous, ranging from asymptomatic and mild upper respiratory tract illness to severe interstitial pneumonia with respiratory failure and even death. Highly age-dependent patterns of immune response potentially explain the higher rates of the severe forms of COVID-19 in elderly patients. However, genetic and epigenetic architecture can influence multiple biological processes during the lifespan, therefore as far as our knowledge shows, vulnerability to viral infection concerning telomere length and epigenetic signature is not a new idea. This review aims is to summarize the current understanding of the role of telomere length and epigenetic mechanisms on the severity of COVID-19. The current knowledge highlights the significant association between the shorter telomere length and the higher risk of developing severe COVID-19. Differential DNA methylation patterns and miRNA expression profiles imply that these hallmarks can play a pivotal role in COVID- 19 pathogenesis. Understanding the causes of inter-individual variations in COVID-19 outcomes could provide clues to the development of the personalized therapeutic intervention.]]>
Wed, 31 Dec 1969 19:00:00 EST
DNA methylation mediated downregulation of histone H3 variant H3.3 affects cell proliferation contributing to the development of HCC. Reddy D, Bhattacharya S, Shah S, Rashid M, Gupta S
Biochim Biophys Acta Mol Basis Dis (01 2022)

Chromatin alterations brought by histone variants and modifications potentially regulate gene transcription from tumor initiation to progression. Histone H3.3 variant is one such epigenetic player important for disease progression and development. Though many studies have implicated H3.3 role in cancer progression and metastasis, its regulation, importance of specific modifications and chaperones have been not understood yet. We report DNA methylation mediated downregulation of histone H3 variant H3.3 in HCC and a concomitant increase in the level of the H3.2 variant. The loss of H3.3 in cancer tissues correlates with a decrease in the histone modifications associated with active transcription like H3K9/K14/K27Ac and H3K4Me3. The ectopic overexpression of H3.3 and H3.2 did not affect global PTMs and cell physiology, probably owing to the deregulation of specific histone chaperones CAF-1 (for H3.2) and HIRA (for H3.3) as observed in HCC tissues. Notably, knockdown of P150, a subunit of CAF-1 leads to a cell cycle arrest in S-phase in a neoplastic rat liver cell line, possibly due to the decrease in the histone levels necessary for DNA packaging. Remarkably, modulation of H3.3 in pre-neoplastic rat liver cells lead to an increase in cell proliferation and a decreased transcription of tumor suppressor genes, recapitulating the tumor cell phenotype. Our data suggests, inhibition of DNA methylation and histone deacetylation leads to the restoration of histone H3 variant expression in tumor cells.]]>
Wed, 31 Dec 1969 19:00:00 EST
Imprinting of canine IGF2 and H19. Brabazon DC, Callanan JJ, Nolan CM
Anim Genet (Feb 2022)

Genomic imprinting occurs in therian mammals and is a phenomenon whereby the two alleles of a gene are differentially expressed, based on the sex of the parent from whom the alleles were inherited. The allelic differences in expression are the consequence of different epigenetic modifications that are established in the sperm or oocyte during gametogenesis and transmitted at fertilization to offspring. A small minority of genes is regulated in this way but they have important biological functions, and aberrant regulation of imprinted genes contributes to disease aetiology in humans and other animals. The factors driving the evolution of imprinted genes are also of considerable interest, as these genes appear to forego the benefits of diploidy. To broaden the phylogenetic analysis of genomic imprinting, we began a study of imprinted genes in the domestic dog, Canis familiaris. In this report, we show that canine IGF2 and H19 are imprinted, with parent-of origin-dependent monoallelic expression patterns in neonatal umbilical cord. We identify a putative imprint control region associated with the genes, and provide evidence for differential methylation of this region in a somatic tissue (umbilical cord) and for its hypermethylation in the male germline. Canis familiaris is fast becoming a highly informative system for elucidating disease processes and evolution, and the study of imprinted genes in this species may help in understanding how these genes contribute to the generation of morphological and behavioral diversity.]]>
Wed, 31 Dec 1969 19:00:00 EST
ASMdb: a comprehensive database for allele-specific DNA methylation in diverse organisms. Zhou Q, Guan P, Zhu Z, Cheng S, Zhou C, Wang H, Xu Q, Sung WK, Li G
Nucleic Acids Res (Jan 2022)

DNA methylation is known to be the most stable epigenetic modification and has been extensively studied in relation to cell differentiation, development, X chromosome inactivation and disease. Allele-specific DNA methylation (ASM) is a well-established mechanism for genomic imprinting and regulates imprinted gene expression. Previous studies have confirmed that certain special regions with ASM are susceptible and closely related to human carcinogenesis and plant development. In addition, recent studies have proven ASM to be an effective tumour marker. However, research on the functions of ASM in diseases and development is still extremely scarce. Here, we collected 4400 BS-Seq datasets and 1598 corresponding RNA-Seq datasets from 47 species, including human and mouse, to establish a comprehensive ASM database. We obtained the data on DNA methylation level, ASM and allele-specific expressed genes (ASEGs) and further analysed the ASM/ASEG distribution patterns of these species. In-depth ASM distribution analysis and differential methylation analysis conducted in nine cancer types showed results consistent with the reported changes in ASM in key tumour genes and revealed several potential ASM tumour-related genes. Finally, integrating these results, we constructed the first well-resourced and comprehensive ASM database for 47 species (ASMdb, www.dna-asmdb.com).]]>
Wed, 31 Dec 1969 19:00:00 EST
Progress in soybean functional genomics over the past decade. Zhang M, Liu S, Wang Z, Yuan Y, Zhang Z, Liang Q, Yang X, Duan Z, Liu Y, Kong F, Liu B, Ren B, Tian Z
Plant Biotechnol J (Feb 2022)

Soybean is one of the most important oilseed and fodder crops. Benefiting from the efforts of soybean breeders and the development of breeding technology, large number of germplasm has been generated over the last 100 years. Nevertheless, soybean breeding needs to be accelerated to meet the needs of a growing world population, to promote sustainable agriculture and to address future environmental changes. The acceleration is highly reliant on the discoveries in gene functional studies. The release of the reference soybean genome in 2010 has significantly facilitated the advance in soybean functional genomics. Here, we review the research progress in soybean omics (genomics, transcriptomics, epigenomics and proteomics), germplasm development (germplasm resources and databases), gene discovery (genes that are responsible for important soybean traits including yield, flowering and maturity, seed quality, stress resistance, nodulation and domestication) and transformation technology during the past decade. At the end, we also briefly discuss current challenges and future directions.]]>
Wed, 31 Dec 1969 19:00:00 EST
Data analysis methods for defining biomarkers from omics data. Li C, Gao Z, Su B, Xu G, Lin X
Anal Bioanal Chem (Jan 2022)

Omics mainly includes genomics, epigenomics, transcriptomics, proteomics and metabolomics. The rapid development of omics technology has opened up new ways to study disease diagnosis and prognosis and to define prospective information of complex diseases. Since omics data are usually large and complex, the method used to analyze the data and to define important information is crucial in omics study. In this review, we focus on advances in biomarker discovery methods based on omics data in the last decade, and categorize them as individual feature analysis, combinatorial feature analysis and network analysis. We also discuss the challenges and perspectives in this field.]]>
Wed, 31 Dec 1969 19:00:00 EST
Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis. Wu F, Xu L, Tu Y, Cheung OK, Szeto LL, Mok MT, Yang W, Kang W, Cao Q, Lai PB, Chan SL, Tan P, Sung JJ, Yip KY, Cheng AS, To KF
Cancer Lett (01 2022)

Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.]]>
Wed, 31 Dec 1969 19:00:00 EST
Context-dependent transcriptional regulation of microglial proliferation. Belhocine S, Machado Xavier A, Distéfano-Gagné F, Fiola S, Rivest S, Gosselin D
Glia (Mar 2022)

Microglia proliferate during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated fundamental aspects of the transcriptional process associated with proliferation of mouse microglia during postnatal development and in adults in a model of induced microglial depletion-repopulation. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1370 genes at higher levels than quiescent microglia. Expression of these may be coordinated by one of two mechanisms of regulation with distinct properties. A first mechanism augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mechanism enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f transcription factors. Of note, transcriptional upregulation of E2f1 and E2f2 family members may represent a critical regulatory checkpoint to enable microglia to achieve efficient cell cycling. Furthermore, analysis of the activity profile of the repertoire of promoter-distal genomic regulatory elements suggests a relatively restricted role for these elements in coordinating cell cycle gene expression in microglia. Overall, proliferating microglia integrates regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.]]>
Wed, 31 Dec 1969 19:00:00 EST
Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress. Liao Y, Chen CH, Xiao T, de la Peña Avalos B, Dray EV, Cai C, Gao S, Shah N, Zhang Z, Feit A, Xue P, Liu Z, Yang M, Lee JH, Xu H, Li W, Mei S, Pierre RS, Shu S, Fei T, Duarte M, Zhao J, Bradner JE, Polyak K, Kantoff PW, Long H, Balk SP, Liu XS, Brown M, Xu K
Proc Natl Acad Sci U S A (Jan 2022)

Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.]]>
Wed, 31 Dec 1969 19:00:00 EST
How paediatric drug development and use could benefit from OMICs: a c4c expert group white paper. Neumann E, Schreeck F, Herberg J, Jacqz Aigrain E, Maitland-van der Zee AH, Pérez-Martínez A, Hawcutt DB, Schaeffeler E, Rane A, de Wildt SN, Schwab M
Br J Clin Pharmacol (Jan 2022)

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates, and infants, is limited by a paucity of good quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts, by complementary information about targeted and non-targeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a sub-division into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as well as type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, non-invasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (e.g. liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, like artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to identify complex phenotypes and subpopulations of patients to improve development of medicines for children with potential economic advantages.]]>
Wed, 31 Dec 1969 19:00:00 EST
Fine mapping with epigenetic information and 3D structure. Orozco G
Semin Immunopathol (Jan 2022)

Since 2005, thousands of genome-wide association studies (GWAS) have been published, identifying hundreds of thousands of genetic variants that increase risk of complex traits such as autoimmune diseases. This wealth of data has the potential to improve patient care, through personalized medicine and the identification of novel drug targets. However, the potential of GWAS for clinical translation has not been fully achieved yet, due to the fact that the functional interpretation of risk variants and the identification of causal variants and genes are challenging. The past decade has seen the development of great advances that are facilitating the overcoming of these limitations, by utilizing a plethora of genomics and epigenomics tools to map and characterize regulatory elements and chromatin interactions, which can be used to fine map GWAS loci, and advance our understanding of the biological mechanisms that cause disease.]]>
Wed, 31 Dec 1969 19:00:00 EST
Regeneration Roadmap: database resources for regenerative biology. Kang W, Jin T, Zhang T, Ma S, Yan H, Liu Z, Ji Z, Cai Y, Wang S, Song M, Ren J, Hu B, Zhou Q, Zhang W, Qu J, Bao Y, Liu GH
Nucleic Acids Res (Jan 2022)

Regeneration plays an instrumental role in biological development and damage repair by constructing and replacing cells, tissues, and organs. Since regenerative capacity declines with age, promoting regeneration is heralded as a potential strategy for delaying aging. On this premise, mechanisms that regulate regeneration have been extensively studied across species and in different tissues. However, an open and comprehensive database collecting and standardizing the abundant data generated in regeneration research, such as high-throughput sequencing data, remains to be developed. In this work, we constructed Regeneration Roadmap to systematically and comprehensively collect such information over 2.38 million data entries across 11 species and 36 tissues, including regeneration-related genes, bulk and single-cell transcriptomics, epigenomics, and pharmacogenomics data. In this database, users can explore regulatory and expression changes of regeneration-associated genes in different species and tissues. Regeneration Roadmap provides the research community with a long-awaited and valuable data resource featuring convenient computing and visualizing tools, which is publicly available at https://ngdc.cncb.ac.cn/regeneration/index.]]>
Wed, 31 Dec 1969 19:00:00 EST
ChromoMap: an R package for interactive visualization of multi-omics data and annotation of chromosomes. Anand L, Rodriguez Lopez CM
BMC Bioinformatics (Jan 2022)

The recent advancements in high-throughput sequencing have resulted in the availability of annotated genomes, as well as of multi-omics data for many living organisms. This has increased the need for graphic tools that allow the concurrent visualization of genomes and feature-associated multi-omics data on single publication-ready plots.]]>
Wed, 31 Dec 1969 19:00:00 EST
Neighborhood characteristics and breast tumor methylation: using epigenomics to explore cancer outcome disparities. Gohar J, Do WL, Miller-Kleinhenz J, Conneely K, Krishnamurti U, D'Angelo O, Gogineni K, Torres M, Gabram-Mendola S, McCullough LE
Breast Cancer Res Treat (Jan 2022)

Social exposures may drive epigenetic alterations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer.]]>
Wed, 31 Dec 1969 19:00:00 EST
2-Hydroxyglutarate destabilizes chromatin regulatory landscape and lineage fidelity to promote cellular heterogeneity. Kusi M, Zand M, Lin LL, Chen M, Lopez A, Lin CL, Wang CM, Lucio ND, Kirma NB, Ruan J, Huang TH, Mitsuya K
Cell Rep (Jan 2022)

The epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of the cancer epigenome remain elusive. Here we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates the high-plasticity chromatin landscape. A combination of single-cell epigenomics and multi-omics approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to the luminal-defining transcriptional factors FOXA1, FOXP1, and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.]]>
Wed, 31 Dec 1969 19:00:00 EST
Clinical Utility of Methylation-Specific Multiplex Ligation-Dependent Probe Amplification for the Diagnosis of Prader-Willi Syndrome and Angelman Syndrome. Kim B, Park Y, Cho SI, Kim MJ, Chae JH, Kim JY, Seong MW, Park SS
Ann Lab Med (Jan 2022)

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of chromosome 15, or an imprinting defect. We evaluated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a diagnostic tool and for demonstrating the relationship between molecular mechanisms and clinical presentation.]]>
Wed, 31 Dec 1969 19:00:00 EST
The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth. Sandovici I, Georgopoulou A, Pérez-García V, Hufnagel A, López-Tello J, Lam BYH, Schiefer SN, Gaudreau C, Santos F, Hoelle K, Yeo GSH, Burling K, Reiterer M, Fowden AL, Burton GJ, Branco CM, Sferruzzi-Perri AN, Constância M
Dev Cell (Jan 2022)

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genome-wide Signatures of Early-Life Stress: Influence of Sex. Parel ST, Peña CJ
Biol Psychiatry (01 2022)

Both history of early-life stress (ELS) and female sex are associated with increased risk for depression. The complexity of how ELS interacts with brain development and sex to impart risk for multifaceted neuropsychiatric disorders is also unlikely to be understood by examining changes in single genes. Here, we review an emerging literature on genome-wide transcriptional and epigenetic signatures of ELS and the potential moderating influence of sex. We discuss evidence both that there are latent sex differences revealed by ELS and that ELS itself produces latent transcriptomic changes revealed by adult stress. In instances where there are broad similarities in global signatures of ELS among females and males, genes that contribute to these patterns are largely distinct based on sex. As this area of investigation grows, an effort should be made to better understand the sex-specific impact of ELS within the human brain, specific contributions of chromosomal versus hormonal sex, how ELS alters the time course of normal transcriptional development, and the cell-type specificity of transcriptomic and epigenomic changes in the brain. A better understanding of how ELS interacts with sex to alter transcriptomic and epigenomic signatures in the brain will inform individualized therapeutic strategies to prevent or ameliorate depression and other psychiatric disorders in this vulnerable population.]]>
Wed, 31 Dec 1969 19:00:00 EST