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https://www.readbyqxmd.com/read/29220567/the-structural-basis-of-the-histone-demethylase-kdm6b-histone-3-lysine-27-specificity
#1
Sarah Elizabeth Jones, Lars Olsen, Michael Gajhede
KDM subfamily 6 enzymes KDM6A and KDM6B specifically catalyse demethylation of di-/tri-methylated lysine on Histone 3 lysine 27 (H3K27me3/2) and play an important role in repression of developmental genes. Despite identical amino acid sequence in the immediate surroundings of H3K9me3/2 (ARKS) the enzymes do not catalyse demethylation of this general marker of repression. In order to address this question for KDM6B we used computational methods to identify H3(17-33) derived peptides with improved binding affinity, that would enable co-crystallization with the catalytic core of human KDM6B (ccKDM6B)...
December 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/29171124/kdm6a-promotes-chondrogenic-differentiation-of-periodontal-ligament-stem-cells-by-demethylation-of-sox9
#2
Pingting Wang, Yanjing Li, Tingting Meng, Junjiang Zhang, Yuanyuan Wei, Zhaosong Meng, Yunfeng Lin, Dayong Liu, Lei Sui
OBJECTIVES: KDM6A has been demonstrated critical in the regulation of cell fates. However, whether KDM6A is involved in cartilage formation remains unclear. In this study, we investigated the role of KDM6A in chondrogenic differentiation of PDLSCs, as well as the underlying epigenetic mechanisms. METHODS: KDM6A shRNA was transfected into PDLSCs by lentivirus. The chondrogenic differentiation potential of PDLSCs was assessed by Alcian blue staining. Immunofluorescence was performed to demonstrate H3K27me3 and H3K4me3 levels during chondrogenesis...
November 23, 2017: Cell Proliferation
https://www.readbyqxmd.com/read/29143738/bladder-cancer-associated-mutations-in-rxra-activate-peroxisome-proliferator-activated-receptors-to-drive-urothelial-proliferation
#3
Angela M Halstead, Chiraag D Kapadia, Jennifer Bolzenius, Clarence E Chu, Andrew Schriefer, Lukas D Wartman, Gregory R Bowman, Vivek K Arora
RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from the TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs...
November 16, 2017: ELife
https://www.readbyqxmd.com/read/29136510/genomic-subtypes-of-non-invasive-bladder-cancer-with-distinct-metabolic-profile-and-female-gender-bias-in-kdm6a-mutation-frequency
#4
Carolyn D Hurst, Olivia Alder, Fiona M Platt, Alastair Droop, Lucy F Stead, Julie E Burns, George J Burghel, Sunjay Jain, Leszek J Klimczak, Helen Lindsay, Jo-An Roulson, Claire F Taylor, Helene Thygesen, Angus J Cameron, Anne J Ridley, Helen R Mott, Dmitry A Gordenin, Margaret A Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29136502/molecular-landscape-of-non-muscle-invasive-bladder-cancer
#5
Joshua J Meeks, Seth P Lerner
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations.
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29108280/trimethylation-of-h3k27-during-human-cerebellar-development-in-relation-to-medulloblastoma
#6
Shahryar E Mir, Michiel Smits, Dennis Biesmans, Machteld Julsing, Marianna Bugiani, Eleonora Aronica, Gertjan J L Kaspers, Jacqueline Cloos, Thomas Würdinger, Esther Hulleman
Medulloblastoma (MB), the most common malignant childhood brain tumor, encompasses a collection of four clinically and molecularly distinct tumor subgroups, i.e. WNT, SHH, Group 3 and Group 4. These tumors are believed to originate from precursor cells during cerebellar development. Although the exact etiology of these brain tumors is not yet known, histone modifications are increasingly recognized as key events during cerebellum development and MB tumorigenesis. Recent studies show that key components involved in post-translational modifications of histone H3 lysine 27 (H3K27) are commonly deregulated in MB...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29073101/utx-guided-neural-crest-function-underlies-craniofacial-features-of-kabuki-syndrome
#7
Karl B Shpargel, Joshua Starmer, Chaochen Wang, Kai Ge, Terry Magnuson
Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29069809/human-papillomavirus-dysregulates-the-cellular-apparatus-controlling-the-methylation-status-of-h3k27-in-different-human-cancers-to-consistently-alter-gene-expression-regardless-of-tissue-of-origin
#8
Steven F Gameiro, Bart Kolendowski, Ali Zhang, John W Barrett, Anthony C Nichols, Joe Torchia, Joe S Mymryk
High-risk human papillomaviruses (HPV) cause cancer at multiple distinct anatomical locations. Regardless of the tissue of origin, most HPV positive (HPV+) cancers show highly upregulated expression of the p16 product of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene. Paradoxically, HPV+ tumor cells require continuous expression of this tumor suppressor for survival. Thus, restoration of normal p16 regulation has potential therapeutic value against HPV induced cancers. Normally, p16 transcription is tightly controlled at the epigenetic level via polycomb repressive complex-mediated tri-methylation of histone 3 lysine 27 (H3K27me3)...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29059780/re-loss-of-tumor-suppressor-kdm6a-amplifies-prc2-regulated-transcriptional-repression-in-bladder-cancer-and-can-be-targeted-through-inhibition-of-ezh2
#9
https://www.readbyqxmd.com/read/29045832/utx-kdm6a-loss-enhances-the-malignant-phenotype-of-multiple-myeloma-and-sensitizes-cells-to-ezh2-inhibition
#10
Teresa Ezponda, Daphné Dupéré-Richer, Christine M Will, Eliza C Small, Nobish Varghese, Tej Patel, Behnam Nabet, Relja Popovic, Jon Oyer, Marinka Bulic, Yupeng Zheng, Xiaoxiao Huang, Mrinal Y Shah, Sayantan Maji, Alberto Riva, Manuela Occhionorelli, Giovanni Tonon, Neil Kelleher, Jonathan Keats, Jonathan D Licht
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29029452/the-h3k27me3-demethylase-kdm6a-is-suppressed-in-breast-cancer-stem-like-cells-and-enables-the-resolution-of-bivalency-during-the-mesenchymal-epithelial-transition
#11
Joseph H Taube, Nathalie Sphyris, Kelsey S Johnson, Keighley N Reisenauer, Taylor A Nesbit, Robiya Joseph, Geraldine V Vijay, Tapasree R Sarkar, Neeraja A Bhangre, Joon Jin Song, Jeffrey T Chang, Min Gyu Lee, Rama Soundararajan, Sendurai A Mani
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28968467/kdm6a-addiction-of-cervical-carcinoma-cell-lines-is-triggered-by-e7-and-mediated-by-p21cip1-suppression-of-replication-stress
#12
David R Soto, Christopher Barton, Karl Munger, Margaret E McLaughlin-Drubin
Expression of E7 proteins encoded by carcinogenic, high-risk human papillomaviruses (HPVs) triggers increased expression of the histone H3 lysine 27 demethylase KDM6A. KDM6A expression is necessary for survival of high-risk HPV E7 expressing cells, including several cervical cancer lines. Here we show that increased KDM6A in response to high-risk HPV E7 expression causes epigenetic de-repression of the cell cycle and DNA replication inhibitor p21CIP1, and p21CIP1 expression is necessary for survival of high-risk HPV E7 expressing cells...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28928876/heterochromatin-reduction-correlates-with-the-increase-of-the-kdm4b-and-kdm6a-demethylases-and-the-expression-of-pericentromeric-dna-during-the-acquisition-of-a-transformed-phenotype
#13
Cinthya Gurrion, Maritere Uriostegui, Mario Zurita
Cancer cells have alterations in chromatin organization, mostly a reduction in heterochromatin. How this process occurs during transformation and if it participates in the maintenance of a cancerous phenotype is not well understood. Here, using a transformation-inducible cell line, we analyzed the changes that occur in heterochromatin during transformation to a cancerous phenotype. After transformation, there is a reduction in heterochromatin bodies and a nuclear reorganization of HP1α. These occurrences correlate with reductions in H3K9me3 and H3K27me3 levels and with some of the enzymes that introduce these modifications...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28887033/long-term-exposure-to-pm2-5-lowers-influenza-virus-resistance-via-down-regulating-pulmonary-macrophage-kdm6a-and-mediates-histones-modification-in-il-6-and-ifn-%C3%AE-promoter-regions
#14
Jing-Hui Ma, Shao-Hua Song, Meng Guo, Ji Zhou, Fang Liu, Li Peng, Zhi-Ren Fu
Atmospheric particulates, especially PM2.5, not only damage the respiratory system, but also play important roles in pulmonary immunity. China is influenced by atmospheric diffusion conditions, industrial manufacturers, and heating and discharging. PM2.5 levels in the air rise substantially in the winter, which is also a period of flu high-incidence. Although an epidemiological link exists between PM2.5 and flu, we do not understand how long-term PM2.5 inhalation affects pulmonary immunity and the influenza virus response...
November 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28884922/congenital-heart-defects-in-molecularly-proven-kabuki-syndrome-patients
#15
Maria Cristina Digilio, Maria Gnazzo, Francesca Lepri, Maria Lisa Dentici, Elisa Pisaneschi, Anwar Baban, Chiara Passarelli, Rossella Capolino, Adriano Angioni, Antonio Novelli, Bruno Marino, Bruno Dallapiccola
The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%)...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28793284/growth-hormone-therapy-in-children-with-kabuki-syndrome-1-year-treatment-results
#16
Dina A Schott, Willem J M Gerver, Constance T R M Stumpel
BACKGROUND/AIMS: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. METHODS: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year...
2017: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/28758283/copy-number-profiling-of-adult-relapsed-b-cell-precursor-acute-lymphoblastic-leukemia-reveals-potential-leukemia-progression-mechanisms
#17
Jordi Ribera, Lurdes Zamora, Mireia Morgades, Mar Mallo, Neus Solanes, Montserrat Batlle, Susana Vives, Isabel Granada, Jordi Juncà, Roberto Malinverni, Eulàlia Genescà, Ramon Guàrdia, Santiago Mercadal, Lourdes Escoda, Joaquín Martinez-Lopez, Mar Tormo, Jordi Esteve, Marta Pratcorona, Carmen Martinez-Losada, Francesc Solé, Evarist Feliu, Josep-Maria Ribera
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays...
July 30, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28747563/the-h3k27me3-demethylase-kdm6a-is-suppressed-in-breast-cancer-stem-like-cells-and-enables-the-resolution-of-bivalency-during-the-mesenchymal-epithelial-transition
#18
Joseph H Taube, Nathalie Sphyris, Kelsey S Johnson, Keighley N Reisenauer, Taylor A Nesbit, Robiya Joseph, Geraldine V Vijay, Tapasree R Sarkar, Neeraja A Bhangre, Joon Jin Song, Jeffrey T Chang, Min Gyu Lee, Rama Soundararajan, Sendurai A Mani
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28725537/the-emerging-role-of-histone-demethylases-in-renal-cell-carcinoma
#19
REVIEW
Xiaoqiang Guo, Qiaoxia Zhang
Renal cell carcinoma (RCC), the most common kidney cancer, is responsible for more than 100,000 deaths per year worldwide. The molecular mechanism of RCC is poorly understood. Many studies have indicated that epigenetic changes such as DNA methylation, noncoding RNAs, and histone modifications are central to the pathogenesis of cancer. Histone demethylases (KDMs) play a central role in histone modifications. There is emerging evidence that KDMs such as KDM3A, KDM5C, KDM6A, and KDM6B play important roles in RCC...
2017: Journal of Kidney Cancer and VHL
https://www.readbyqxmd.com/read/28712054/alcohol-exposure-promotes-dna-methyltransferase-dnmt3a-upregulation-through-reactive-oxygen-species-dependent-mechanisms
#20
Federico Miozzo, Hélène Arnould, Aurélie de Thonel, Anne-Laure Schang, Délara Sabéran-Djoneidi, Anne Baudry, Benoît Schneider, Valérie Mezger
Abundant evidence has accumulated showing that fetal alcohol exposure broadly modifies DNA methylation profiles in the brain. DNA methyltransferases (DNMTs), the enzymes responsible for DNA methylation, are likely implicated in this process. However, their regulation by ethanol exposure has been poorly addressed. Here, we show that alcohol exposure modulates DNMT protein levels through multiple mechanisms. Using a neural precursor cell line and primary mouse embryonic fibroblasts (MEFs), we found that ethanol exposure augments the levels of Dnmt3a, Dnmt3b, and Dnmt3l transcripts...
July 15, 2017: Cell Stress & Chaperones
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