'; ?> 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 Fri, 22 Feb 2019 03:43:19 EST Fri, 22 Feb 2019 03:43:19 EST jirtle@radonc.duke.edu james001@jirtle.com Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. Karbassi E, Rosa-Garrido M, Chapski DJ, Wu Y, Ren S, Wang Y, Stefani E, Vondriska TM
J Mol Cell Cardiol (Feb 2019)

Heart failure is associated with hypertrophying of cardiomyocytes and changes in transcriptional activity. Studies from rapidly dividing cells in culture have suggested that transcription may be compartmentalized into factories within the nucleus, but this phenomenon has not been tested in vivo and the role of nuclear architecture in cardiac gene regulation is unknown. While alterations to transcription have been linked to disease, little is known about the regulation of the spatial organization of transcription and its properties in the pathological setting. In the present study, we investigate the structural features of endogenous transcription factories in the heart and determine the principles connecting chromatin structure to transcriptional regulation in vivo. Super-resolution imaging of endogenous RNA polymerase II clusters in neonatal and adult cardiomyocytes revealed distinct properties of transcription factories in response to pathological stress: neonatal nuclei demonstrated changes in number of clusters, with parallel increases in nuclear area, while the adult nuclei underwent changes in size and intensity of RNA polymerase II foci. Fluorescence in situ hybridization-based labeling of genes revealed locus-specific relationships between expression change and anatomical localization-with respect to nuclear periphery and heterochromatin regions, both sites associated with gene silencing-in the nuclei of cardiomyocytes in hearts (but not liver hepatocytes) of mice subjected to pathologic stimuli that induce heart failure. These findings demonstrate a role for chromatin organization and rearrangement of nuclear architecture for cell type-specific transcription in vivo during disease. RNA polymerase II ChIP and chromatin conformation capture studies in the same model system demonstrate formation and reorganization of distinct nuclear compartments regulating gene expression. These findings reveal locus-specific compartmentalization of stress-activated, housekeeping and silenced genes in the anatomical context of the endogenous nucleus, revealing basic principles of global chromatin structure and nuclear architecture in the regulation of gene expression in healthy and diseased conditions.]]>
Wed, 31 Dec 1969 19:00:00 EST
miR-126 regulates glycogen trophoblast proliferation and DNA methylation in the murine placenta. Sharma A, Lacko LA, Argueta LB, Glendinning MD, Stuhlmann H
Dev Biol (Feb 2019)

A functional placenta develops through a delicate interplay of its vascular and trophoblast compartments. We have identified a previously unknown expression domain for the endothelial-specific microRNA miR-126 in trophoblasts of murine and human placentas. Here, we determine the role of miR-126 in placental development using a mouse model with a targeted deletion of miR-126. In addition to vascular defects observed only in the embryo, loss of miR-126 function in the placenta leads to junctional zone hyperplasia at E15.5 at the expense of the labyrinth, reduced placental volume for nutrient exchange and intra-uterine growth restriction of the embryos. Junctional zone hyperplasia results from increased numbers of proliferating glycogen trophoblast (GlyT) progenitors at E13.5 that give rise to an expanded glycogen trophoblast population at E15.5. Transcriptomic profile of miR-126 placentas revealed dysregulation of a large number of GlyT (Prl6a1, Prl7c1, Pcdh12) and trophoblast-specific genes (Tpbpa, Tpbpb, Prld1) and genes with known roles in placental development. We show that miR-126 placentas, but not miR-126 embryos, display aberrant expression of imprinted genes with important roles in glycogen trophoblasts and junctional zone development, including Igf2, H19, Cdkn1c and Phlda2, during mid-gestation. We also show that miR126 placentas display global hypermethylation, including at several imprint control centers. Our findings uncover a novel role for miR-126 in regulating extra-embryonic energy stores, expression of imprinted genes and DNA methylation in the placenta.]]>
Wed, 31 Dec 1969 19:00:00 EST
Paediatrician's guide to epigenetics. Byrne L, Drake AJ
Arch Dis Child (Mar 2019)

Epigenetic regulation of gene expression is critical for normal development. Dysregulation of the epigenome can lead to the development and progression of a number of diseases relevant to paediatricians, including disorders of genomic imprinting and malignancies. It has long been recognised that early life events have implications for future disease risk, and epigenetic modifications may play a role in this, although further high-quality research is needed to better understand the underlying mechanisms. Research in the field of epigenetics will contribute to a greater understanding of growth, development and disease; however, paediatricians need to be able to interpret such research critically, in order to use the potential advances brought about through epigenetic studies while appreciating their limitations.]]>
Wed, 31 Dec 1969 19:00:00 EST
A bipartite boundary element restricts imprinting to mature neurons. Hsiao JS, Germain ND, Wilderman A, Stoddard C, Wojenski LA, Villafano GJ, Core L, Cotney J, Chamberlain SJ
Proc Natl Acad Sci U S A (Feb 2019)

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of , a gene encoding an E3 ubiquitin ligase. is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of is restricted to neurons by expression of () from the paternally inherited allele, which silences the paternal allele of in However, the mechanism restricting expression and imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of in humans. Removal of this element led to up-regulation of without repressing paternal However, increasing expression of in the absence of the boundary element resulted in full repression of paternal , demonstrating that imprinting requires both the loss of function from the boundary element as well as the up-regulation of These results suggest that manipulation of the competition between and may provide a potential therapeutic approach for AS.]]>
Wed, 31 Dec 1969 19:00:00 EST
New frontiers in precision medicine for sepsis-induced immunoparalysis. Bruse N, Leijte GP, Pickkers P, Kox M
Expert Rev Clin Immunol (Mar 2019)

In the last decade, the sepsis research field has shifted focus from targeting hyperinflammation to reversing sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis is very heterogeneous: the magnitude and the nature of the underlying immune defects differ considerably between patients, but also within individuals over time. Therefore, a 'one-treatment-fits-all' strategy for sepsis-induced immunoparalysis is bound to fail, and an individualized 'precision medicine' approach is required. Such a strategy is nevertheless hampered by the unsuitability of the currently available markers to identify the many immune defects that can manifest in individual patients. Areas covered: We describe the currently available markers for sepsis-induced immunoparalysis and limitations pertaining to their use. Furthermore, future prospects and caveats are discussed, focusing on 'omics' approaches: genomics, transcriptomics, epigenomics, and metabolomics. Finally, we present a contemporary overview of adjuvant immunostimulatory therapies. Expert opinion: The integration of multiple omics techniques offers a systems biology approach which can yield biomarker profiles that accurately and comprehensively gauge the extent and nature of sepsis-induced immunoparalysis. We expect this development to be instrumental in facilitating precision medicine for sepsis-induced immunoparalysis, consisting of the application of targeted immunostimulatory therapies and follow-up measurements to monitor the response to treatment and to titrate or adjust medication.]]>
Wed, 31 Dec 1969 19:00:00 EST
Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood. Bavineni M, Wassenaar TM, Agnihotri K, Ussery DW, Lüscher TF, Mehta JL
Eur Heart J (Feb 2019)

Cardiovascular disease (CVD) rates in adulthood are high in premature infants; unfortunately, the underlying mechanisms are not well defined. In this review, we discuss potential pathways that could lead to CVD in premature babies. Studies show intense oxidant stress and inflammation at tissue levels in these neonates. Alterations in lipid profile, foetal epigenomics, and gut microbiota in these infants may also underlie the development of CVD. Recently, probiotic bacteria, such as the mucin-degrading bacterium Akkermansia muciniphila have been shown to reduce inflammation and prevent heart disease in animal models. All this information might enable scientists and clinicians to target pathways to act early to curtail the adverse effects of prematurity on the cardiovascular system. This could lead to primary and secondary prevention of CVD and improve survival among preterm neonates later in adult life.]]>
Wed, 31 Dec 1969 19:00:00 EST
Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics. Rowland J, Akbarov A, Eales J, Xu X, Dormer JP, Guo H, Denniff M, Jiang X, Ranjzad P, Nazgiewicz A, Prestes PR, Antczak A, Szulinska M, Wise IA, Zukowska-Szczechowska E, Bogdanski P, Woolf AS, Samani NJ, Charchar FJ, Tomaszewski M
Kidney Int (Mar 2019)

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.]]>
Wed, 31 Dec 1969 19:00:00 EST
Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules. Zviran A, Mor N, Rais Y, Gingold H, Peles S, Chomsky E, Viukov S, Buenrostro JD, Scognamiglio R, Weinberger L, Manor YS, Krupalnik V, Zerbib M, Hezroni H, Jaitin DA, Larastiaso D, Gilad S, Benjamin S, Gafni O, Mousa A, Ayyash M, Sheban D, Bayerl J, Aguilera-Castrejon A, Massarwa R, Maza I, Hanna S, Stelzer Y, Ulitsky I, Greenleaf WJ, Tanay A, Trumpp A, Amit I, Pilpel Y, Novershtern N, Hanna JH
Cell Stem Cell (Feb 2019)

The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes. The pluripotency module is governed by dynamic alterations in epigenetic modifications to promoters and binding by Oct4, Sox2, and Klf4, but not Myc. Early DNA demethylation at certain enhancers prospectively marks cells fated to reprogram. Myc activity drives expression of the essential biosynthetic module and is associated with optimized changes in tRNA codon usage. Our functional validations highlight interweaved epigenetic- and Myc-governed essential reconfigurations that rapidly commission and propel deterministic reprogramming toward naive pluripotency.]]>
Wed, 31 Dec 1969 19:00:00 EST
Parent-of-origin effects on carcass traits in Japanese Black cattle. Okamoto K, Oishi K, Nakamura R, Abe A, Inoue K, Kumagai H, Hirooka H
J Anim Breed Genet (Feb 2019)

Variances caused by the differential expression of paternally and maternally imprinted genes controlling carcass traits in Japanese Black cattle were estimated in this study. Data on marbling score (BMS), carcass weight, rib thickness, rib-eye area (REA) and subcutaneous fat thickness (SFT) were collected from a total of 13,115 feedlot steers and heifers in a commercial population. A sire-maternal grandsire model was used to analyse the data, and then, imprinting parameters were derived by replacing the genetic effect of the dam with the effect of the maternal grandsire in the imprinting model to calculate the genetic parameter estimates. The proportions of the total genetic variance attributable to imprinted genes ranged from 8.7% (SFT) to 35.2% (BMS). The remarkably large imprinting variance of BMS was mainly contributed by maternally expressed inheritance because the maternal contribution of the trait was much larger than that of the paternal trait. The parent-of-origin effect originating from maternal gene expression was also observed for REA. The results suggested the existence of genomic imprinting effects on the traits of the Japanese Black cattle. Hence, the parent-of-origin effect should be considered for the genetic evaluation of Japanese Black cattle in breeding programmes.]]>
Wed, 31 Dec 1969 19:00:00 EST
Link between depression and cardiovascular diseases due to epigenomics and proteomics: Focus on energy metabolism. Kahl KG, Stapel B, Frieling H
Prog Neuropsychopharmacol Biol Psychiatry (Mar 2019)

Major depression is the most common mental disorder and a leading cause of years lived with disability. In addition to the burden attributed to depressive symptoms and reduced daily life functioning, people with major depression are at increased risk of premature mortality, particularly due to cardiovascular diseases. Several studies point to a bi-directional relation between major depression and cardiovascular diseases, thereby indicating that both diseases may share common pathophysiological pathways. These include lifestyle factors (e.g. physical activity, smoking behavior), dysfunctions of endocrine systems (e.g. hypothalamus-pituitary adrenal axis), and a dysbalance of pro- and anti-inflammatory factors. Furthermore, recent research point to the role of epigenomic and proteomic factors, that are reviewed here with a particular focus on the mitochondrial energy metabolism.]]>
Wed, 31 Dec 1969 19:00:00 EST
Comparative 3D genome organization in apicomplexan parasites. Bunnik EM, Venkat A, Shao J, McGovern KE, Batugedara G, Worth D, Prudhomme J, Lapp SA, Andolina C, Ross LS, Lawres L, Brady D, Sinnis P, Nosten F, Fidock DA, Wilson EH, Tewari R, Galinski MR, Ben Mamoun C, Ay F, Le Roch KG
Proc Natl Acad Sci U S A (Feb 2019)

The positioning of chromosomes in the nucleus of a eukaryotic cell is highly organized and has a complex and dynamic relationship with gene expression. In the human malaria parasite , the clustering of a family of virulence genes correlates with their coordinated silencing and has a strong influence on the overall organization of the genome. To identify conserved and species-specific principles of genome organization, we performed Hi-C experiments and generated 3D genome models for five species and two related apicomplexan parasites. species mainly showed clustering of centromeres, telomeres, and virulence genes. In , the heterochromatic virulence gene cluster had a strong repressive effect on the surrounding nuclear space, while this was less pronounced in and , and absent in In , telomeres and virulence genes were more dispersed throughout the nucleus, but its 3D genome showed a strong correlation with gene expression. The genome showed a classical Rabl organization with colocalization of subtelomeric virulence genes, while the genome was dominated by clustering of the centromeres and lacked virulence gene clustering. Collectively, our results demonstrate that spatial genome organization in most species is constrained by the colocalization of virulence genes. and , the only two species with gene families involved in antigenic variation, are unique in the effect of these genes on chromosome folding, indicating a potential link between genome organization and gene expression in more virulent pathogens.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse. Ngo V, Chen Z, Zhang K, Whitaker JW, Wang M, Wang W
Proc Natl Acad Sci U S A (Feb 2019)

Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNA-binding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.]]>
Wed, 31 Dec 1969 19:00:00 EST
Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function. Hall IF, Climent M, Quintavalle M, Farina FM, Schorn T, Zani S, Carullo P, Kunderfranco P, Civilini E, Condorelli G, Elia L
Circ Res (Feb 2019)

microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown.]]>
Wed, 31 Dec 1969 19:00:00 EST
Comprehensive, integrated, and phased whole-genome analysis of the primary ENCODE cell line K562. Zhou B, Ho SS, Greer SU, Zhu X, Bell JM, Arthur JG, Spies N, Zhang X, Byeon S, Pattni R, Ben-Efraim N, Haney MS, Haraksingh RR, Song G, Ji HP, Perrin D, Wong WH, Abyzov A, Urban AE
Genome Res (Feb 2019)

K562 is widely used in biomedical research. It is one of three tier-one cell lines of ENCODE and also most commonly used for large-scale CRISPR/Cas9 screens. Although its functional genomic and epigenomic characteristics have been extensively studied, its genome sequence and genomic structural features have never been comprehensively analyzed. Such information is essential for the correct interpretation and understanding of the vast troves of existing functional genomics and epigenomics data for K562. We performed and integrated deep-coverage whole-genome (short-insert), mate-pair, and linked-read sequencing as well as karyotyping and array CGH analysis to identify a wide spectrum of genome characteristics in K562: copy numbers (CN) of aneuploid chromosome segments at high-resolution, SNVs and indels (both corrected for CN in aneuploid regions), loss of heterozygosity, megabase-scale phased haplotypes often spanning entire chromosome arms, structural variants (SVs), including small and large-scale complex SVs and nonreference retrotransposon insertions. Many SVs were phased, assembled, and experimentally validated. We identified multiple allele-specific deletions and duplications within the tumor suppressor gene Taking aneuploidy into account, we reanalyzed K562 RNA-seq and whole-genome bisulfite sequencing data for allele-specific expression and allele-specific DNA methylation. We also show examples of how deeper insights into regulatory complexity are gained by integrating genomic variant information and structural context with functional genomics and epigenomics data. Furthermore, using K562 haplotype information, we produced an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize K562 as well as a framework for the analysis of other cancer genomes.]]>
Wed, 31 Dec 1969 19:00:00 EST
Allele-specific RNA-seq expression profiling of imprinted genes in mouse isogenic pluripotent states. Dirks RAM, van Mierlo G, Kerstens HHD, Bernardo AS, Kobolák J, Bock I, Maruotti J, Pedersen RA, Dinnyés A, Huynen MA, Jouneau A, Marks H
Epigenetics Chromatin (02 2019)

Genomic imprinting, resulting in parent-of-origin specific gene expression, plays a critical role in mammalian development. Here, we apply allele-specific RNA-seq on isogenic B6D2F1 mice to assay imprinted genes in tissues from early embryonic tissues between E3.5 and E7.25 and in pluripotent cell lines to evaluate maintenance of imprinted gene expression. For the cell lines, we include embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) derived from fertilized embryos and from embryos obtained after nuclear transfer (NT) or parthenogenetic activation (PGA).]]>
Wed, 31 Dec 1969 19:00:00 EST
The cis-Regulatory Atlas of the Mouse Immune System. Yoshida H, Lareau CA, Ramirez RN, Rose SA, Maier B, Wroblewska A, Desland F, Chudnovskiy A, Mortha A, Dominguez C, Tellier J, Kim E, Dwyer D, Shinton S, Nabekura T, Qi Y, Yu B, Robinette M, Kim KW, Wagers A, Rhoads A, Nutt SL, Brown BD, Mostafavi S, Buenrostro JD, Benoist C,  
Cell (Feb 2019)

A complete chart of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of differentiation and function of an organ system. We generated matched epigenome and transcriptome measurements in 86 primary cell types that span the mouse immune system and its differentiation cascades. This breadth of data enable variance components analysis that suggests that genes fall into two distinct classes, controlled by either enhancer- or promoter-driven logic, and multiple regression that connects genes to the enhancers that regulate them. Relating transcription factor (TF) expression to the genome-wide accessibility of their binding motifs classifies them as predominantly openers or closers of local chromatin accessibility, pinpointing specific cis-regulatory elements where binding of given TFs is likely functionally relevant, validated by chromatin immunoprecipitation sequencing (ChIP-seq). Overall, this cis-regulatory atlas provides a trove of information on transcriptional regulation through immune differentiation and a foundational scaffold to define key regulatory events throughout the immunological genome.]]>
Wed, 31 Dec 1969 19:00:00 EST
Human Genetic Adaptation to High Altitude: Evidence from the Andes. Julian CG, Moore LG
Genes (Basel) (Feb 2019)

Whether Andean populations are genetically adapted to high altitudes has long been of interest. Initial studies focused on physiological changes in the O₂ transport system that occur with acclimatization in newcomers and their comparison with those of long-resident Andeans. These as well as more recent studies indicate that Andeans have somewhat larger lung volumes, narrower alveolar to arterial O₂ gradients, slightly less hypoxic pulmonary vasoconstrictor response, greater uterine artery blood flow during pregnancy, and increased cardiac O utilization, which overall suggests greater efficiency of O₂ transfer and utilization. More recent single nucleotide polymorphism and whole-genome sequencing studies indicate that multiple gene regions have undergone recent positive selection in Andeans. These include genes involved in the regulation of vascular control, metabolic hemostasis, and erythropoiesis. However, fundamental questions remain regarding the functional links between these adaptive genomic signals and the unique physiological attributes of highland Andeans. Well-designed physiological and genome association studies are needed to address such questions. It will be especially important to incorporate the role of epigenetic processes (i.e.; non-sequence-based features of the genome) that are vital for transcriptional responses to hypoxia and are potentially heritable across generations. In short, further exploration of the interaction among genetic, epigenetic, and environmental factors in shaping patterns of adaptation to high altitude promises to improve the understanding of the mechanisms underlying human adaptive potential and clarify its implications for human health.]]>
Wed, 31 Dec 1969 19:00:00 EST
Maternal regulation of chromosomal imprinting in animals. Singh PB, Shloma VV, Belyakin SN
Chromosoma (Feb 2019)

Chromosomal imprinting requires an epigenetic system that "imprints" one of the two parental chromosomes such that it results in a heritable (cell-to-cell) change in behavior of the "imprinted" chromosome. Imprinting takes place when the parental genomes are separate, which occurs during gamete formation in the respective germ-lines and post-fertilization during the period when the parental pro-nuclei lie separately within the ooplasm of the zygote. In the mouse, chromosomal imprinting is regulated by germ-line specific DNA methylation. But the methylation machinery in the respective germ-lines does not discriminate between imprinted and non-imprinted regions. As a consequence, the mouse oocyte nucleus contains over a thousand oocyte-specific germ-line differentially methylated regions (gDMRs). Upon fertilization, the sperm provides a few hundred sperm-specific gDMRs of its own. Combined, there are around 1600 imprinted and non-imprinted gDMRs in the pro-nuclei of the newly fertilized zygote. It is a remarkable fact that beginning in the maternal ooplasm, there are mechanisms that manage to preserve DNA methylation at ~ 26 known imprinted gDMRs in the face of the ongoing genome-wide DNA de-methylation that characterizes pre-implantation development. Specificity is achieved through the binding of KRAB-zinc finger proteins to their cognate recognition sequences within the gDMRs of imprinted genes. This in turn nucleates the assembly of localized heterochromatin-like complexes that preserve methylation at imprinted gDMRs through recruitment of the maintenance methyl transferase Dnmt1. These studies have shown that a germ-line imprint may cause parent-of-origin-specific behavior only if "licensed" by mechanisms that operate post-fertilization. Study of the germ-line and post-fertilization contributions to the imprinting of chromosomes in classical insect systems (Coccidae and Sciaridae) show that the ooplasm is the likely site where imprinting takes place. By comparing molecular and genetic studies across these three species, we suggest that mechanisms which operate post-fertilization play a key role in chromosomal imprinting phenomena in animals and conserved components of heterochromatin are shared by these mechanisms.]]>
Wed, 31 Dec 1969 19:00:00 EST
The peculiar aging of human liver: A geroscience perspective within transplant context. Morsiani C, Bacalini MG, Santoro A, Garagnani P, Collura S, D'Errico A, de Eguileor M, Grazi GL, Cescon M, Franceschi C, Capri M
Ageing Res Rev (Feb 2019)

An appraisal of recent data highlighting aspects inspired by the new Geroscience perspective are here discussed. The main findings are summarized as follows: i) liver has to be considered an immunological organ, and new studies suggest a role for the recently described cells named telocytes; ii) the liver-gut axis represents a crucial connection with environment and life style habits and may influence liver diseases onset; iii) the physiological aging of liver shows relatively modest alterations. Nevertheless, several molecular changes appear to be relevant: a) an increase of microRNA-31-5p; -141-3p; -200c-3p expressions after 60 years of age; b) a remodeling of genome-wide DNA methylation profile evident until 60 years of age and then plateauing; c) changes in transcriptome including the metabolic zones of hepatocyte lobules; d) liver undergoes an accelerated aging in presence of chronic inflammation/liver diseases in a sort of continuum, largely as a consequence of unhealthy life styles and exposure to environmental noxious agents. We argue that chronic liver inflammation has all the major characteristics of "inflammaging" and likely sustains the onset and progression of liver diseases. Finally, we propose to use a combination of parameters, mostly obtained by omics such as transcriptomics and epigenomics, to evaluate in deep both the biological age of liver (in comparison with the chronological age) and the effects of donor-recipient age-mismatches in the context of liver transplants.]]>
Wed, 31 Dec 1969 19:00:00 EST
Consistent Reanalysis of Genome-wide Imprinting Studies in Plants Using Generalized Linear Models Increases Concordance across Datasets. Wyder S, Raissig MT, Grossniklaus U
Sci Rep (Feb 2019)

Genomic imprinting leads to different expression levels of maternally and paternally derived alleles. Over the last years, major progress has been made in identifying novel imprinted candidate genes in plants, owing to affordable next-generation sequencing technologies. However, reports on sequencing the transcriptome of hybrid F1 seed tissues strongly disagree about how many and which genes are imprinted. This raises questions about the relative impact of biological, environmental, technical, and analytic differences or biases. Here, we adopt a statistical approach, frequently used in RNA-seq data analysis, which properly models count overdispersion and considers replicate information of reciprocal crosses. We show that our statistical pipeline outperforms other methods in identifying imprinted genes in simulated and real data. Accordingly, reanalysis of genome-wide imprinting studies in Arabidopsis and maize shows that, at least for Arabidopsis, an increased agreement across datasets could be observed. For maize, however, consistent reanalysis did not yield a larger overlap between the datasets. This suggests that the discrepancy across publications might be partially due to different analysis pipelines but that technical, biological, and environmental factors underlie much of the discrepancy between datasets. Finally, we show that the set of genes that can be characterized regarding allelic bias by all studies with minimal confidence is small (~8,000/27,416 genes for Arabidopsis and ~12,000/39,469 for maize). In conclusion, we propose to use biologically replicated reciprocal crosses, high sequence coverage, and a generalized linear model approach to identify differentially expressed alleles in developing seeds.]]>
Wed, 31 Dec 1969 19:00:00 EST