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
Biochemistry & Molecular Biology
Jiuwei Lu, Jian Fang, Hongtao Zhu, Kimberly Lu Liang, Nelli Khudaverdyan, Jikui Song
Summary: This study reveals the mechanism of allosteric regulation and dynamic assembly of DNMT3B by investigating its cryo-EM structure under different oligomerization states. The interaction between the ADD domain and the MTase domain of DNMT3B forms an autoinhibitory conformation, similar to the previously observed DNMT3A autoinhibition. The PWWP domain and its associated ICF mutation are found to play a role in the allosteric regulation of DNMT3B tetramer, and the bindings of ADD-H3K4me0 and PWWP-H3K36me3 have differential functional impacts on DNMT3B.
NUCLEIC ACIDS RESEARCH
(2023)
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
Cell Biology
Yingying Meng, Guliang Wang, Hongjuan He, Kin H. Lau, Allison Hurt, Brianna J. Bixler, Andrea Parham, Seung-Gi Jin, Xingzhi Xu, Karen M. Vasquez, Gerd P. Pfeifer, Piroska E. Szabo
Summary: A biological process that erases Z-DNA specifically in germ cells of the mouse male foetus has been discovered, which is mediated by a previously uncharacterized zinc finger protein, ZBTB43. This process prevents DNA double-strand breaks and promotes de novo DNA methylation, ensuring genomic and epigenomic integrity.
NATURE CELL BIOLOGY
(2022)
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
Cell Biology
Raghav Ramabadran, Jarey H. Wang, Jaime M. Reyes, Anna G. Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C. Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M. Cullen, Siddhartha Tyagi, Danielle Rux, Jean J. Kim, Steven M. Kornblau, Michael Kyba, Fabio Stossi, Rachel E. Rau, Koichi Takahashi, Thomas F. Westbrook, Margaret A. Goodell
Summary: Ramabadran et al. discovered that upon extrinsic stimulation, stem cells activate a program involving increased splicing efficiency mediated by DNMT3A and recruitment of SF3B1 to RNA polymerase and mRNA, promoting the activation of embryonic and hematopoietic stem cells. This DNA methylation-independent role of DNMT3A in stem cell activation and splicing regulation provides new insights into the mechanisms governing stem cell differentiation.
NATURE CELL BIOLOGY
(2023)
Article
Biology
Shan Qi, Javier Mota, Siu-Hong Chan, Johanna Villarreal, Nan Dai, Shailee Arya, Robert A. Hromas, Manjeet K. Rao, Ivan R. Correa, Yogesh K. Gupta
Summary: The METTL3-METTL14 complex catalyzes methylation of RNA and DNA, with a preference for single-stranded DNA and structured RNA, respectively. The complex has a higher affinity for structured RNA but methylates RNA less efficiently than DNA. Furthermore, the methylation of DNA by the complex is restricted by structured RNA elements prevalent in cellular RNAs.
Review
Pharmacology & Pharmacy
Zhixiong Zhang, Guan Wang, Yuyan Li, Dongsheng Lei, Jin Xiang, Liang Ouyang, Yanyan Wang, Jinliang Yang
Summary: DNA methylation is an important epigenetic process that regulates gene expression and has become a promising target for cancer treatment.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Analytical
Zhen Liu, Keyun Wang, Mingliang Ye
Summary: In order to understand the function of protein arginine methyltransferases(PRMTs), it is crucial to identify their substrate proteins. However, this is challenging due to the dominance of stable and strong interacting proteins over weak and transient substrate proteins. In this study, a novel photoreactive probe-based strategy was developed to identify the substrate proteins of methyltransferases, specifically PRMT1. This strategy effectively distinguished substrate proteins from other interacting proteins and allowed the identification of highly confident substrate proteins. Importantly, it was discovered that hypomethylation of proteins is a prerequisite for efficient capturing of substrate proteins. This study describes the development of a robust chemical proteomic tool for profiling transient substrates and has broad biomedical applications.
ANALYTICAL CHEMISTRY
(2023)
Article
Medicine, General & Internal
Katarina Lopusna, Pawel Nowialis, Jana Opavska, Ajay Abraham, Alberto Riva, Rene Opavsky
Summary: The study revealed that Dnmt3b's catalytic activity is largely dispensable for mouse development but critical for preventing tumorigenesis by controlling events involved in cellular transformation. The lack of Dnmt3b's catalytic activity promoted fibroblast transformation in vitro and accelerated the development of certain types of leukemia and lymphoma in vivo.
Article
Biochemistry & Molecular Biology
Shang Liang, Joana C. Silva, Olga Suska, Radoslaw Lukoszek, Rajaei Almohammed, Victoria H. Cowling
Summary: CMTR1 plays a critical role in RNA expression and differentiation, particularly in histone and ribosomal protein gene regulation. Repression of CMTR1 leads to decreased RNA expression, translation inhibition, and induction of DNA replication stress and damage. CMTR1 is upregulated during neural differentiation and is essential for gene expression and proliferation during this process.
NUCLEIC ACIDS RESEARCH
(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
Biochemistry & Molecular Biology
Nicholas Z. Lue, Emma M. Garcia, Kevin C. Ngan, Ceejay Lee, John G. Doench, Brian B. Liau
Summary: In this study, we use base editing and a DNA methylation reporter to scan mutations of DNMT3A in situ in cells. We identify mutations throughout the protein that disrupt function, including mutations at the interdomain interface that block allosteric activation. Surprisingly, we also find mutations in the PWWP domain that modulate enzyme activity by affecting DNA affinity.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Clinical Neurology
Bo Hao, Bu Fang Fan, Can-Can Cao, Lu Liu, Shou-Min Xuan, Li Wang, Zhen-Jie Gao, Yan-Wei Shi, Xiao-Guang Wang, Hu Zhao
Summary: Fear memory is critical for individual survival, but maladaptive fear response is a hallmark of fear-related disorders. This study reveals the role of nucleus accumbens (NAc) and DNA methylation in fear discrimination. Inhibition of DNA methyltransferase 3a gene (DNMT3a) in NAc leads to a maladaptive fear response, while whole-genome bisulfite sequencing (WGBS) identifies differentially methylated sites and genes related to synaptic function and cGMP-PKG signaling pathway.
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
(2023)
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
Multidisciplinary Sciences
Erna Davydova, Tadahiro Shimazu, Maren Kirstin Schuhmacher, Magnus E. Jakobsson, Hanneke L. D. M. Willemen, Tongri Liu, Anders Moen, Angela Y. Y. Ho, Jedrzej Malecki, Lisa Schroer, Rita Pinto, Takehiro Suzuki, Ida A. Gronsberg, Yoshihiro Sohtome, Mai Akakabe, Sara Weirich, Masaki Kikuchi, Jesper V. Olsen, Naoshi Dohmae, Takashi Umehara, Mikiko Sodeoka, Valentina Siino, Michael A. McDonough, Niels Eijkelkamp, Christopher J. Schofield, Albert Jeltsch, Yoichi Shinkai, Pal O. Falnes
Summary: Post-translational methylation, specifically protein histidine methylation, is crucial for optimizing protein function. METTL9 is identified as a broad-specificity methyltransferase responsible for the majority of 1-methylhistidine modifications in mouse and human proteomes. The methylation catalyzed by METTL9 enhances respiration via Complex I, and reduces the zinc binding affinity of HxH-containing peptides.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Viviane Klingel, Jakob Kirch, Timo Ullrich, Sara Weirich, Albert Jeltsch, Nicole E. Radde
Summary: The study developed a novel mathematical model to describe the switching dynamics of methylation-based epigenetic memory systems, which revealed a high sensitivity to variations in temperature. A moderate decrease in temperature led to a highly heterogeneous response to input signals and bistability on a single-cell level, confirming the model's predictions.
Article
Biochemistry & Molecular Biology
Sabine Pinter, Franziska Knodel, Michel Choudalakis, Philipp Schnee, Carolin Kroll, Marina Fuchs, Alexander Broehm, Sara Weirich, Mareike Roth, Stephan A. Eisler, Johannes Zuber, Albert Jeltsch, Philipp Rathert
Summary: In this study, we identified DEAD-box helicase 19A (DDX19A) as a novel coregulator of lysine specific demethylase 1 (LSD1), which regulates gene expression by controlling the trimethylation of lysine 27 on histone 3. This discovery sheds light on a novel transcriptional regulatory pathway involving LSD1, DDX19A, and histone modifications.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biology
Sabrina Adam, Julia Bracker, Viviane Klingel, Bernd Osteresch, Nicole E. Radde, Jens Brockmeyer, Pavel Bashtrykov, Albert Jeltsch
Summary: This study reveals that the catalytic activities of TET1 and TET2 are influenced by the flanking sequences of DNA substrates, and this influence is related to 5mC and 5hmC. Furthermore, enhanced flanking sequence preferences and profound effects on the specificity of TET2 are observed at non-CpG sites. The flanking sequence preferences of TET are reflected in genome-wide and local patterns of 5hmC and DNA demethylation.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Alexandra Mack, Max Emperle, Philipp Schnee, Sabrina Adam, Juergen Pleiss, Pavel Bashtrykov, Albert Jeltsch
Summary: Somatic R882H DNMT3A mutations are common in AML, but their pathogenic mechanism is unclear. R882H mutations affect the sequence preferences of DNMT3A and have a dominant effect on its catalytic properties in samples containing WT and R882H subunits.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biology
Alexander Broehm, Tabea Schoch, Michael Dukatz, Nora Graf, Franziska Dorscht, Evelin Mantai, Sabrina Adam, Pavel Bashtrykov, Albert Jeltsch
Summary: DNMT3A efficiently methylates recombinant mononucleosome linker DNA, and H3K36me3 stimulates linker DNA methylation independent of its interaction with the PWWP domain.
COMMUNICATIONS BIOLOGY
(2022)
Editorial Material
Biology
Arunkumar Dhayalan, Albert Jeltsch
Article
Biochemistry & Molecular Biology
Alexander Broehm, Tabea Schoch, David Gruenberger, Mina S. Khella, Maren Kirstin Schuhmacher, Sara Weirich, Albert Jeltsch
Summary: The H3.3 G34W mutation is commonly found in giant cell tumor of bone (GCTB) patients and is associated with reduced SETD2 activity and global reduction in DNA methylation. Our study reveals that the G34W mutation enhances the activity of NSD1 methyltransferase, but has mild effects on NSD2. We discuss the potential downstream effects of the G34W-induced hyperactivity of NSD1 on DNA methylation, histone modifications, and splicing.
Article
Chemistry, Multidisciplinary
Philipp Schnee, Michel Choudalakis, Sara Weirich, Mina S. Khella, Henrique Carvalho, Juergen Pleiss, Albert Jeltsch
Summary: This study investigates the mechanisms responsible for the increased activity of SETD2 towards ssK36 peptide. Molecular dynamics simulations and biochemical experiments reveal that ssK36 adopts a hairpin conformation in solution and unfolds during the association process with SETD2. Introducing a stable hairpin conformation increases the methylation of H3K36 peptide by SETD2.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Stefan Kunert, Max Emperle, Sabrina Adam, Julia Bracker, Jens Bracker, Arumugam Rajavelu, Albert Jeltsch
Summary: The DNMT3A DNA methyltransferase is frequently mutated in cancers, especially in AML. The R736H mutation in the FF-interface of the enzyme leads to a moderate reduction in catalytic activity but no changes in CpG specificity or sub-nuclear localization. DNMT3L strongly stimulates the activity of R736H, and mixed interfaces involving R736H also enhance the activity.
Article
Biochemistry & Molecular Biology
Dimitri Graf, Laura Laistner, Viviane Klingel, Nicole E. Radde, Sara Weirich, Albert Jeltsch
Summary: A DNA methylation-based epigenetic memory system was developed to detect environmental signals and trigger phenotypic switches in bacteria. The system's reversible reset was achieved by adding ZnSO4, and the long-term stability of the ON-state was studied, showing a gradual loss of signal over time.
Article
Biology
Julian Broche, Anja R. R. Koehler, Fiona Kuehnel, Bernd Osteresch, Thyagarajan T. T. Chandrasekaran, Sabrina Adam, Jens Brockmeyer, Albert Jeltsch
Summary: Although cytosine-C5 methylation of DNA is essential in higher eukaryotes, the presence and importance of 6-methyladenine (m6dA) in human cells are controversial. We introduced m6dA in human cells and observed reductions in cell viability, particularly after global GANTC methylation. Genes directly regulated by m6dA in a GANTC context showed changes in H3K27me3 and JUN family transcription factor binding, indicating an inhibitory effect on the PRC2 complex and reduced recruitment of JUN transcription factors. Our study demonstrates the physiological effects of m6dA introduction in human DNA and identifies target genes and molecular pathways that affect gene expression and cell phenotypes.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sabrina Adam, Viviane Klingel, Nicole E. Radde, Pavel Bashtrykov, Albert Jeltsch
Summary: The specificity of DNMT1 for hemimethylated DNA is strongly influenced by the flanking sequence, with an average specificity of 80-fold. This preference is enhanced on long hemimethylated DNA substrates. The presence of a single methyl group in the DNA changes the conformation of the DNMT1-DNA complex, leading to an active conformation by steric repulsion. Passive DNA demethylation by 5hmC generation is not efficient in many flanking contexts.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Genetics & Heredity
Nivethika Rajaram, Alexandra G. Kouroukli, Susanne Bens, Pavel Bashtrykov, Albert Jeltsch
Summary: Specific allele-specific targeted DNA methylation was achieved at multiple gene loci using epigenome editing, which can be potentially applied in the treatment of diseases caused by dominant mutations with minimal side effects.
EPIGENETICS & CHROMATIN
(2023)
Editorial Material
Multidisciplinary Sciences
Sara Weirich, Albert Jeltsch
Summary: Protein lysine methylation is important but lacks suitable mimetics for experimental characterization. This limits biochemical and cellular studies. We summarize the challenges and propose alternative approaches.
NATURE COMMUNICATIONS
(2023)