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https://www.readbyqxmd.com/read/29765957/genetic-insights-into-frailty-association-of-9p21-23-locus-with-frailty
#1
Sanish Sathyan, Nir Barzilai, Gil Atzmon, Sofiya Milman, Emmeline Ayers, Joe Verghese
Frailty is a complex aging phenotype associated with increased vulnerability to disability and death. Understanding the biological antecedents of frailty may provide clues to healthy aging. The genome-wide association study hotspot, 9p21-23 region, is a risk locus for a number of age-related complex disorders associated with frailty. Hence, we conducted an association study to examine whether variations in 9p21-23 locus plays a role in the pathogenesis of frailty in 637 community-dwelling Ashkenazi Jewish adults aged 65 and older enrolled in the LonGenity study...
2018: Frontiers in Medicine
https://www.readbyqxmd.com/read/29760161/ctcf-boundary-remodels-chromatin-domain-and-drives-aberrant-hox-gene-transcription-in-acute-myeloid-leukemia
#2
Huacheng Luo, Fei Wang, Jie Zha, Haoli Li, Bowen Yan, Qinghua Du, Fengchun Yang, Amin Sobh, Christopher Vulpe, Leylah Drusbosky, Christopher Cogle, Iouri Chepelev, Bing Xu, Stephen D Nimer, Jonathan Licht, Yi Qiu, Baoan Chen, Mingjiang Xu, Suming Huang
HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene expression patterns within confined chromatin domains for normal development. Here, we employed targeted pooled CRISPR-Cas9 knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci...
May 14, 2018: Blood
https://www.readbyqxmd.com/read/29757144/computational-prediction-of-ctcf-cohesin-based-intra-tad-loops-that-insulate-chromatin-contacts-and-gene-expression-in-mouse-liver
#3
Bryan J Matthews, David J Waxman
CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues...
May 14, 2018: ELife
https://www.readbyqxmd.com/read/29728444/emerging-evidence-of-chromosome-folding-by-loop-extrusion
#4
Geoffrey Fudenberg, Nezar Abdennur, Maxim Imakaev, Anton Goloborodko, Leonid A Mirny
Chromosome organization poses a remarkable physical problem with many biological consequences: How can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase...
May 4, 2018: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29723654/ctcf-knockout-reveals-an-essential-role-for-this-protein-during-the-zebrafish-development
#5
Francisco Carmona-Aldana, Cecilia Zampedri, Fernando Suaste-Olmos, Adrián Murillo-de-Ozores, Georgina Guerrero, Rodrigo Arzate-Mejía, Ernesto Maldonado, Rosa Navarro, Jesús Chimal-Monroy, Félix Recillas-Targa
Chromatin regulation and organization are essential processes that regulate gene activity. The CCCTC-binding factor (CTCF) is a protein with different and important molecular functions related with chromatin dynamics. It is conserved since invertebrates to vertebrates, posing it as a factor with an important role in the physiology. In this work, we aimed to understand the distribution and functional relevance of CTCF during the embryonic development of the zebrafish (Danio rerio). We generated a zebrafish specific anti-Ctcf antibody, and found this protein to be ubiquitous, through different stages and tissues...
May 1, 2018: Mechanisms of Development
https://www.readbyqxmd.com/read/29712785/remote-memory-and-cortical-synaptic-plasticity-require-neuronal-ccctc-binding-factor-ctcf
#6
Somi Kim, Nam-Kyung Yu, Kyu-Won Shim, Ji-Il Kim, Hyopil Kim, Dae Hee Han, Ja Eun Choi, Seung-Woo Lee, Dong Il Choi, Myung Won Kim, Dong-Sung Lee, Kyungmin Lee, Niels Galjart, Yong-Seok Lee, Jae-Hyung Lee, Bong-Kiun Kaang
The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the three-dimensional (3D) chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation are still largely unknown...
April 30, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29712779/dopamine-triggers-ctcf-dependent-morphological-and-genomic-remodeling-of-astrocytes
#7
Ashley Galloway, Adewale Adeluyi, Bernadette O'Donovan, Miranda L Fisher, Chintada Nageswara Rao, Peyton Critchfield, Mathew Sajish, Jill R Turner, Pavel I Ortinski
Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well-established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead, relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on astrocytic voltage-gated potassium channel currents...
April 30, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29706548/the-energetics-and-physiological-impact-of-cohesin-extrusion
#8
Laura Vian, Aleksandra Pękowska, Suhas S P Rao, Kyong-Rim Kieffer-Kwon, Seolkyoung Jung, Laura Baranello, Su-Chen Huang, Laila El Khattabi, Marei Dose, Nathanael Pruett, Adrian L Sanborn, Andres Canela, Yaakov Maman, Anna Oksanen, Wolfgang Resch, Xingwang Li, Byoungkoo Lee, Alexander L Kovalchuk, Zhonghui Tang, Steevenson Nelson, Michele Di Pierro, Ryan R Cheng, Ido Machol, Brian Glenn St Hilaire, Neva C Durand, Muhammad S Shamim, Elena K Stamenova, José N Onuchic, Yijun Ruan, Andre Nussenzweig, David Levens, Erez Lieberman Aiden, Rafael Casellas
Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA...
April 24, 2018: Cell
https://www.readbyqxmd.com/read/29706538/hmgb2-loss-upon-senescence-entry-disrupts-genomic-organization-and-induces-ctcf-clustering-across-cell-types
#9
Anne Zirkel, Milos Nikolic, Konstantinos Sofiadis, Jan-Philipp Mallm, Chris A Brackley, Henrike Gothe, Oliver Drechsel, Christian Becker, Janine Altmüller, Natasa Josipovic, Theodore Georgomanolis, Lilija Brant, Julia Franzen, Mirjam Koker, Eduardo G Gusmao, Ivan G Costa, Roland T Ullrich, Wolfgang Wagner, Vassilis Roukos, Peter Nürnberg, Davide Marenduzzo, Karsten Rippe, Argyris Papantonis
Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, imaging, and in silico modeling of three distinct cells types entering senescence. Genes involved in DNA conformation maintenance are suppressed upon senescence entry across all cell types...
April 20, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29706346/an-osteoporosis-risk-snp-at-1p36-12-acts-as-an-allele-specific-enhancer-to-modulate-linc00339-expression-via-long-range-loop-formation
#10
Xiao-Feng Chen, Dong-Li Zhu, Man Yang, Wei-Xin Hu, Yuan-Yuan Duan, Bing-Jie Lu, Yu Rong, Shan-Shan Dong, Ruo-Han Hao, Jia-Bin Chen, Yi-Xiao Chen, Shi Yao, Hlaing Nwe Thynn, Yan Guo, Tie-Lin Yang
Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region...
April 14, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29702522/three-dimensional-genome-organization-in-normal-and-malignant-haematopoiesis
#11
Sergi Cuartero, Matthias Merkenschlager
PURPOSE OF REVIEW: The three-dimensional organization of the genome inside the nucleus impacts on key aspects of genome function, including transcription, DNA replication and repair. The chromosome maintenance complex cohesin and the DNA binding protein CTCF cooperate to drive the formation of self-interacting topological domains. This facilitates transcriptional regulation via enhancer-promoter interactions, controls the distribution and release of torsional strain, and affects the frequency with which particular translocations arise, based on the spatial proximity of translocation partners...
April 26, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29698677/long-noncoding-rna-hottip-cooperates-with-ccctc-binding-factor-to-coordinate-hoxa-gene-expression
#12
Feng Wang, Zhongqiong Tang, Honglian Shao, Jun Guo, Tao Tan, Yang Dong, Lianbing Lin
The spatiotemporal control of HOX gene expression is dependent on positional identity and often correlated to their genomic location within each loci. Maintenance of HOX expression patterns is under complex transcriptional and epigenetic regulation, which is not well understood. Here we demonstrate that HOTTIP, a lincRNA transcribed from the 5' edge of the HOXA locus, physically associates with the CCCTC-binding factor (CTCF) that serves as an insulator by organizing HOXA cluster into disjoint domains, to cooperatively maintain the chromatin modifications of HOXA genes and thus coordinate the transcriptional activation of distal HOXA genes in human foreskin fibroblasts...
April 23, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29688601/de-novo-mutations-in-the-set-nuclear-proto-oncogene-encoding-a-component-of-the-inhibitor-of-histone-acetyltransferases-inhat-complex-in-patients-with-non-syndromic-intellectual-disability
#13
Servi Jc Stevens, Vyne van der Schoot, Magalie S Leduc, Tuula Rinne, Seema R Lalani, Marjan M Weiss, Johanna M van Hagen, Augusta Ma Lachmeijer, Sylvia G Stockler-Ipsiroglu, Anna Lehman, Han G Brunner
The role of disturbed chromatin remodelling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the "SET nuclear proto-oncogene" (SET), encoding a component of the "inhibitor of acetyltransferases" (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29688244/retinoic-acid-and-ctcf-play-key-roles-in-inducing-the-collinear-expression-of-the-hoxa-cluster
#14
Ji Hoon Oh, Clara Yuri Kim, Ji-Yeon Lee, Myoung Hee Kim
During the development of an embryo, the initiation of the collinear expression of Hox genes is essential for the proper formation of the anteroposterior body axis. Retinoic acid (RA), a natural derivative of vitamin A, plays a role in vertebrate development by regulating Hox gene expression. CCCTC-binding factor (CTCF), an insulator protein that controls gene transcription, also regulates the expression of Hox genes by binding to the CTCF-binding sites (CBSs). It has been reported that upon RA signaling, retinoic acid response elements (RAREs) located in the Hox clusters become occupied...
April 23, 2018: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29685368/principles-of-chromosome-architecture-revealed-by-hi-c
#15
REVIEW
Kyle P Eagen
Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops...
April 20, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29682202/ctcf-kdm4a-complex-correlates-with-histone-modifications-that-negatively-regulate-chd5-gene-expression-in-cancer-cell-lines
#16
Lissania Guerra-Calderas, Rodrigo González-Barrios, Carlos César Patiño, Nicolás Alcaraz, Marisol Salgado-Albarrán, David Cantú de León, Clementina Castro Hernández, Yesennia Sánchez-Pérez, Héctor Aquiles Maldonado-Martínez, Inti A De la Rosa-Velazquez, Fernanda Vargas-Romero, Luis A Herrera, Alejandro García-Carrancá, Ernesto Soto-Reyes
Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. KDM4A is abnormally expressed in cancer, affecting the expression of multiple targets, such as the CHD5 gene. This enzyme localizes at the first intron of CHD5 , and the dissociation of KDM4A increases gene expression. In vitro assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity in vivo, however the specific mechanism by which CTCF and KDM4A might be involved in the CHD5 gene repression is poorly understood...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29670109/mutation-hotspots-at-ctcf-binding-sites-coupled-to-chromosomal-instability-in-gastrointestinal-cancers
#17
Yu Amanda Guo, Mei Mei Chang, Weitai Huang, Wen Fong Ooi, Manjie Xing, Patrick Tan, Anders Jacobsen Skanderup
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs)...
April 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29610276/the-transcriptional-regulator-ccctc-binding-factor-limits-oxidative-stress-in-endothelial-cells
#18
Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish, Paul Delgado Olguin
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 owing to defective yolk sac and placental vascular development...
April 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29593713/variable-extent-of-lineage-specificity-and-developmental-stage-specificity-of-cohesin-and-ccctc-binding-factor-binding-within-the-immunoglobulin-and-t-cell-receptor-loci
#19
Salvatore Loguercio, E Mauricio Barajas-Mora, Han-Yu Shih, Michael S Krangel, Ann J Feeney
CCCTC-binding factor (CTCF) is largely responsible for the 3D architecture of the genome, in concert with the action of cohesin, through the creation of long-range chromatin loops. Cohesin is hypothesized to be the main driver of these long-range chromatin interactions by the process of loop extrusion. Here, we performed ChIP-seq for CTCF and cohesin in two stages each of T and B cell differentiation and examined the binding pattern in all six antigen receptor (AgR) loci in these lymphocyte progenitors and in mature T and B cells, ES cells, and fibroblasts...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29590048/nascent-dna-methylome-mapping-reveals-inheritance-of-hemimethylation-at-ctcf-cohesin-sites
#20
Chenhuan Xu, Victor G Corces
The faithful inheritance of the epigenome is critical for cells to maintain gene expression programs and cellular identity across cell divisions. We mapped strand-specific DNA methylation after replication forks and show maintenance of the vast majority of the DNA methylome within 20 minutes of replication and inheritance of some hemimethylated CpG dinucleotides (hemiCpGs). Mapping the nascent DNA methylome targeted by each of the three DNA methyltransferases (DNMTs) reveals interactions between DNMTs and substrate daughter cytosines en route to maintenance methylation or hemimethylation...
March 9, 2018: Science
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