Article
Multidisciplinary Sciences
David Y. Chen, Ian M. Ferguson, Krista A. Braun, Leslie A. Sutton, Nichole M. Helton, Sai Mukund Ramakrishnan, Amanda M. Smith, Christopher A. Miller, Timothy J. Ley
Summary: DNA hypomethylation is a characteristic of epidermal cells from aged and sun-exposed skin, with Dnmt3a deficiency potentially creating a premalignant state in the skin by increasing susceptibility to transformation through proliferative gene expression. DNMT3A loss may lead to a hyperproliferative phenotype and act as a tumor suppressor in the skin.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Ni Yan, Yuntong Li, Yangfei Xing, Jiale Wu, Jiabing Li, Ying Liang, Yigang Tang, Zhengyuan Wang, Huaxin Song, Haoyu Wang, Shujun Xiao, Min Lu
Summary: This study establishes a mouse model of developmental arsenic exposure and finds that arsenic exposure leads to deficits in recognition and spatial memory in the offspring. These deficits are associated with DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. The study also reveals that arsenic atoms directly bind to the ADD domain of DNMT3A, leading to its degradation and genome-wide DNA hypomethylation.
Article
Biochemistry & Molecular Biology
Andrei G. Loiko, Alexander Sergeev, Adelya Genatullina, Mayya Monakhova, Elena A. Kubareva, Nina G. Dolinnaya, Elizaveta S. Gromova
Summary: This study reveals a potential link between G-quadruplex formation and the function of DNA methyltransferase Dnmt3a in mammals. G4s may play a role in epigenetic regulation by affecting the methylation of specific CpG sites and modulating the enzyme activity. Possible mechanisms include sequestration of Dnmt3a at G4 structures and disruption of Dnmt3a oligomerization on DNA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G. Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A. Goodell
Summary: This study reveals the essential role of the long isoform (DNMT3A1) of DNA methyltransferase 3a (DNMT3A) in mouse postnatal development. DNMT3A1 specifically regulates bivalent neurodevelopmental genes in the brain. The N terminus of DNMT3A1 is shown to be necessary for normal development and DNA methylation at DNMT3A1-enriched regions, possibly through binding to mono-ubiquitinated histone H2AK119. These findings provide insights into the isoform-specific functions and regulatory mechanisms of DNMT3A in development.
Article
Chemistry, Physical
Adrian Fernandez-de-la-Pradilla, Santiago Royo, Tanja Schirmeister, Fabian Barthels, Katarzyna Swiderek, Florenci V. Gonzalez, Vicent Moliner
Summary: This study focuses on the design and characterization of potential inhibitors of Cathepsin L (CatL) and their inhibitory mechanism. The results demonstrate the effectiveness of the designed compounds in inhibiting CatL and highlight the importance of the structural features of the compounds in enzyme inhibition. The findings provide valuable insights for the design of inhibitors and the development of drugs for cancer treatment.
Article
Biology
Ayala Tovy, Jaime M. Reyes, Linda Zhang, Yung-Hsin Huang, Carina Rosas, Alexes C. Daquinag, Anna Guzman, Raghav Ramabadran, Chun-Wei Chen, Tianpeng Gu, Sinjini Gupta, Laura Ortinau, Dongsu Park, Aaron R. Cox, Rachel E. Rau, Sean M. Hartig, Mikhail G. Kolonin, Margaret A. Goodell
Summary: DNMT3A plays a crucial role in the differentiation of embryonic and hematopoietic stem cells. Heterozygous mutations in DNMT3A lead to Tatton-Brown-Rahman syndrome, characterized by obesity and excessive height. This study shows that DNMT3A affects feeding behavior and adipocyte progenitor differentiation, contributing to the development of inflammatory obesity.
Article
Biochemistry & Molecular Biology
Sara Zocher, Rupert W. Overall, Gabriel Berdugo-Vega, Nicole Rund, Anne Karasinsky, Vijay S. Adusumilli, Christina Steinhauer, Sina Scheibenstock, Kristian Handler, Joachim L. Schultze, Federico Calegari, Gerd Kempermann
Summary: Newborn DNA methylation during adult neurogenesis is crucial for the maturation and integration of functional neurons in the hippocampus, facilitating transcriptional up-regulation of neuronal genes and affecting activation patterns in the hippocampal circuitry.
Article
Biochemistry & Molecular Biology
Feilong Wang, Zuliang Qin, Zhiqiang Li, Shuangyi Yang, Tian Gao, Lina Sun, Deshou Wang
Summary: In this study, the precise expression patterns of dnmt3aa and dnmt3ab in tilapia gonads were elucidated. Mutation of dnmt3aa and dnmt3ab were achieved, showing that dnmt3aa(-/-) mutants exhibited lower GSI, increased apoptosis, and reduced sperm quality, while dnmt3ab(-/-) mutants displayed normal gonadal development. Results suggest that dnmt3aa, but not dnmt3ab, plays important roles in maintaining gametogenesis in teleosts.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Morten Tulstrup, Mette Soerensen, Jakob Werner Hansen, Linn Gillberg, Maria Needhamsen, Katja Kaastrup, Kristian Helin, Kaare Christensen, Joachim Weischenfeldt, Kirsten Gronbaek
Summary: TET2 mutations are associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients. These hypermethylated sites are associated with leukocyte function, immune response, as well as ETS-related and C/EBP-related transcription factor motifs.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Darya Kaplun, Alexey Starshin, Fedor Sharko, Kristina Gainova, Galina Filonova, Nadezhda Zhigalova, Alexander Mazur, Egor Prokhortchouk, Svetlana Zhenilo
Summary: The gain and loss of DNA methylation in cells is a dynamic process that tends to reach equilibrium. Kaiso, in addition to being a methyl DNA binding protein, may attract methyltransferases to surrounding regions and modulate genome methylation in cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Stefan Kunert, Verena Linhard, Sara Weirich, Michel Choudalakis, Florian Osswald, Lisa Kraemer, Anja R. Koehler, Alexander Broehm, Jan Wollenhaupt, Harald Schwalbe, Albert Jeltsch
Summary: The highly expressed DNMT3A DNA methyltransferase and MECP2 methylation reader in neurons interact through their DNMT3A-ADD and MECP2-TRD domains, and the interaction between MECP2 regulates the activity and subnuclear localization of DNMT3A. The interface of these two domains was mapped, revealing that the ADD domain interacts with the TRD domain through the D529-D531 region, while the TRD domain interacts with the ADD domain through residues 214-228, including K219 and K223. The mutations at the ADD-TRD interface disrupt the cellular interaction of these proteins in NIH3T3 cells.
Article
Biochemistry & Molecular Biology
Yucheng Zhong, Jing Liu, Xiangyu Cheng, Hao Zhang, Chunhua Zhang, Zhuolu Xia, Zhongxi Wu, Lu Zhang, Yuting Zheng, Zhanyu Gao, Zhidong Jiang, Zhixiang Wang, Dechun Huang, Yuanyuan Lu, Feng Jiang
Summary: A series of novel phenazine derivatives containing Michael acceptor scaffolds were designed and synthesized in this study, with compound 26 showing the best antiproliferative activity against Bel-7402 cancer cells. Compound 26 was found to inhibit TrxR1 enzyme activity, leading to apoptosis through the ROS-Trx-ASK1-p38 pathway.
BIOORGANIC CHEMISTRY
(2021)
Article
Biology
Junhao Li, Antonio Pinto-Duarte, Mark Zander, Michael S. Cuoco, Chi-Yu Lai, Julia Osteen, Linjing Fang, Chongyuan Luo, Jacinta D. Lucero, Rosa Gomez-Castanon, Joseph R. Nery, Isai Silva-Garcia, Yan Pang, Terrence J. Sejnowski, Susan B. Powell, Joseph R. Ecker, Eran A. Mukamel, M. Margarita Behrens
Summary: Two epigenetic pathways, DNA methylation and PRC2, play important roles in neuronal development. This study found that loss of Dnmt3a affects synapse-related gene expression, impairs synapse maturation, and leads to working memory and social interest deficits. Genomic analysis revealed an unmethylated epigenomic pattern resembling fetal neurons in adult neurons upon loss of Dnmt3a.
Article
Multidisciplinary Sciences
Hiroshi Sakai, Yuichiro Sawada, Naohito Tokunaga, Kaori Tanaka, So Nakagawa, Iori Sakakibara, Yusuke Ono, So-Ichiro Fukada, Yasuyuki Ohkawa, Tadahiko Kikugawa, Takashi Saika, Yuuki Imai
Summary: DNA methylation is crucial for regulating cellular identity, and the epigenetic regulator Uhrf1 plays a critical role in the proliferation and differentiation of satellite cells in muscle regeneration by controlling cell-type-specific gene expression through maintenance of DNA methylation.
Article
Cell Biology
Peng Liu, Jin-Pin Liu, Si-Jia Sun, Yun Gao, Yingjie Ai, Xiufei Chen, Yiping Sun, Mengyu Zhou, Yun Liu, Yue Xiong, Hai-Xin Yuan
Summary: Aberrant DNA methylation is associated with various human diseases, including cancer. The CBFB-MYH11 fusion gene in AML mutually excludes DNMT3A mutations and affects DNA methylation and gene expression.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Dany Pechalrieu, Daniel Dauzonne, Paola B. Arimondo, Marie Lopez
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Multidisciplinary
Flore Nardella, Ludovic Halby, Elie Hammam, Diane Erdmann, Veronique Cadet-Daniel, Roger Peronet, Didier Menard, Benoit Witkowski, Salah Mecheri, Artur Scherf, Paola B. Arimondo
ACS CENTRAL SCIENCE
(2020)
Article
Chemistry, Multidisciplinary
Matthew G. Alteen, Christina Gros, Richard W. Meek, David A. Cardoso, Jil A. Busmann, Gontran Sangouard, Matthew C. Deen, Hong-Yee Tan, David L. Shen, Cecilia C. Russell, Gideon J. Davies, Phillip J. Robinson, Adam McCluskey, David J. Vocadlo
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2020)
Article
Oncology
Clemens Zwergel, Rossella Fioravanti, Giulia Stazi, Federica Sarno, Cecilia Battistelli, Annalisa Romanelli, Angela Nebbioso, Eduarda Mendes, Alexandra Paulo, Raffaele Strippoli, Marco Tripodi, Dany Pechalrieu, Paola B. Arimondo, Teresa De Luca, Donatella Del Bufalo, Daniela Trisciuoglio, Lucia Altucci, Sergio Valente, Antonello Mai
Article
Biochemistry & Molecular Biology
Dany Pechalrieu, Fanny Assemat, Ludovic Halby, Marlene Marcellin, Pengrong Yan, Karima Chaoui, Sahil Sharma, Gabriela Chiosis, Odile Burlet-Schiltz, Paola B. Arimondo, Marie Lopez
ACS CHEMICAL BIOLOGY
(2020)
Article
Chemistry, Organic
Omar Castillo-Aguilera, Patrick Depreux, Alexia Ballee, Florian Beaurain, Paola B. Arimondo, Laurence Goossens
Review
Oncology
Clemence Topart, Emilie Werner, Paola B. Arimondo
CLINICAL EPIGENETICS
(2020)
Editorial Material
Genetics & Heredity
Corentin Bon, Ludovic Halby, Paola Barbara Arimondo
Article
Plant Sciences
Isabelle Pouny, Christophe Long, Muriel Batut, Yannick Aussagues, Naubron Jean Valere, Gaston Achoundong, Bruno David, Catherine Lavaud, Georges Massiot
Summary: Five new quinolizidine alkaloids, named cylicomorphins A-E, were isolated from the leaves of Cylicomorpha solmstii. They are all ester derivatives of the same basic quinolizidine skeleton and exhibit cytotoxicity against HCT-116 cell line.
JOURNAL OF NATURAL PRODUCTS
(2021)
Article
Chemistry, Medicinal
Flore Nardella, Ludovic Halby, Irina Dobrescu, Johanna Viluma, Corentin Bon, Aurelie Claes, Veronique Cadet-Daniel, Ambre Tafit, Camille Roesch, Elie Hammam, Diane Erdmann, Melissa Mairet-Khedim, Roger Peronet, Salah Mecheri, Benoit Witkowski, Artur Scherf, Paola B. Arimondo
Summary: The newly developed derivatives combining pan-histone deacetylase inhibitor with DNA methyltransferase inhibitor show superior activity in treating malaria and potent inhibition against human HDAC6. These compounds are fully active against multidrug-resistant Plasmodium and offer a cost-effective alternative to current failing antimalarial therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Corentin Bon, Magdalena Barbachowska, Nemanja Djokovic, Dusan Ruzic, Yang Si, Laura Soresinetti, Corinne Jallet, Ambre Tafit, Ludovic Halby, Katarina Nikolic, Paola B. Arimondo
Summary: In this study, the authors used molecular docking to design new bisubstrate inhibitors of DOT1L. They found that quinazoline can replace adenine and show similar activity with reduced cytotoxicity.
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Samy Cecioni, Roger A. Ashmus, Pierre-Andre Gilormini, Sha Zhu, Xi Chen, Xiaoyang Shan, Christina Gros, Matthew C. Deen, Yang Wang, Robert Britton, David J. Vocadlo
Summary: Understanding the function and regulation of enzymes within cells requires quality tools to report their activities. This article introduces a strategy for quantitatively monitoring enzyme activities within live cells and describes the design and synthesis of fluorescence-quenched substrates for sensitive quantitation. The substrates can be used to measure the engagement of target enzymes by inhibitors and the efficiency of pharmacological chaperones, highlighting the importance of quantifying activity within cells.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Biology
Pierre-Marie Allard, Arnaud Gaudry, Luis-Manuel Quiros-Guerrero, Adriano Rutz, Miwa Dounoue-Kubo, Tom W. N. Walker, Emmanuel Defossez, Christophe Long, Antonio Grondin, Bruno David, Jean-Luc Wolfender
Summary: As privileged structures, natural products often exhibit potent biological activities. However, the complexity of the biological matrices they are found in often hinders the discovery of novel bioactive scaffolds. Large natural extract collections are valuable for their chemical novelty potential but challenging to exploit in drug discovery projects. Establishing digital layers documenting the complexity and bioactivity of these collections can help prioritize isolation efforts. In this study, the exploration of a collection of 1,600 plant extracts for drug discovery purposes is presented, including taxonomic coverage, liquid chromatography high-resolution mass spectrometric profiling, and computational solutions for data analysis. The resulting dataset and metadata are made available for researchers interested in computational natural products exploration.
