Article
Multidisciplinary Sciences
Kenneth Wu, Namrita Dhillon, Kelvin Du, Rohinton T. Kamakaka
Summary: Gene silencing in budding yeast is maintained by unacetylated nucleosomes and requires 50% to 75% acetylation for activation. The Sir4 gene is a key component in maintaining gene silencing, with even a two-fold reduction in acetyltransferases potentially leading to transcriptional silence.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Oncology
Yan Yi, Shenglei Ge
Summary: This article reviews the recent advances and future trends of therapeutic strategies against DOT1L for MLL-rearranged leukemias, and discusses the limitations, challenges, and prospects of these strategies. DOT1L, as a therapeutic target for MLL-rearranged leukemias, holds important research and development value.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Biology
Christopher J. Petell, Kathyrn Randene, Michael Pappas, Diego Sandoval, Brian D. Strahl, Joseph S. Harrison, Joshua P. Steimel
Summary: The METRIS assay leverages the concept of friction to measure protein-protein interaction affinities, offering high resolution and sensitivity. It allows for the measurement of a wide range of affinities with a small amount of reagents, providing new insights into epigenetic recognition.
Article
Multidisciplinary Sciences
Dakota L. Jones, Grey F. Hallstroem, Xi Jiang, Ryan C. Locke, Mary Kate Evans, Edward D. Bonnevie, Anjana Srikumar, Thomas P. Leahy, Madhura P. Nijsure, Joel D. Boerckel, Robert L. Mauck, Nathaniel A. Dyment
Summary: Cells integrate mechanical cues to maintain tissue function and homeostasis, but the underlying mechanisms are not well understood. This study shows that loss of tensile cues changes nuclear morphology, positioning, and gene expression, resulting in weakening of tendons.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Alfonso Carlos Barragan-Rosillo, Carlos Alberto Peralta-Alvarez, Jonathan Odilon Ojeda-Rivera, Rodrigo G. Arzate-Mejia, Felix Recillas-Targa, Luis Herrera-Estrella
Summary: Plants have evolved strategies to cope with phosphorus scarcity, with genetic approaches identifying key regulators like PHR1 and PHL2 in the transcriptional response to phosphate starvation. Chromatin accessibility undergoes genome-wide remodeling in root cells during Pi starvation, with PHR1 and PHL2 playing a crucial role in this process. These transcription factors directly activate a second wave of epigenetic changes needed for the transcriptional activation of low-Pi-responsive genes in Pi-starved root cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Alexander Munden, Mary Lauren Benton, John A. Capra, Jared T. Nordman
Summary: R-loops play important roles in various biological processes. This study reveals that R-loop abundance and genome localization change during Drosophila embryogenesis and that RNaseH1 activity is crucial for embryonic development. The findings also demonstrate the developmental plasticity of R-loops in gene formation and their relative positioning.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bismark Appiah, Camila L. Fullio, Chiara Ossola, Ilaria Bertani, Elena Restelli, Arquimedes Cheffer, Martina Polenghi, Christiane Haffner, Marta Garcia-Miralles, Patrice Zeis, Martin Treppner, Patrick Bovio, Laura Schlichtholz, Aina Mas-Sanchez, Lea Zografidou, Jennifer Winter, Harald Binder, Dominic Gruen, Nereo Kalebic, Elena Taverna, Tanja Vogel
Summary: Cortical neurogenesis relies on the balance between self-renewal and differentiation of apical progenitors (APs). This study investigates the epigenetic control of AP's division mode by examining the enzymatic activity of histone methyltransferase DOT1L. The findings reveal that DOT1L inhibition promotes neurogenesis by causing a shift in APs from asymmetric self-renewing to symmetric neurogenic consumptive divisions, and this is mediated by the regulation of asparagine metabolism.
Article
Developmental Biology
Aushaq B. Malla, Shannon R. Rainsford, Zachary D. Smith, Bluma J. Lesch
Summary: Unique chromatin remodeling factors regulate nuclear morphology changes during sperm differentiation. Histone-to-protamine exchange is a critical step in this process, and the histone methyltransferase DOT1L plays an essential role in this transition. Loss of DOT1L leads to abnormal sperm head formation and male sterility, due to impaired histone replacement and protamine recruitment. DOT1L also affects transcriptional regulation and gene expression during sperm differentiation.
Article
Cell Biology
Hyunjin Yoo, Hyeonwoo La, Chanhyeok Park, Seonho Yoo, Hyeonji Lee, Hyuk Song, Jeong Tae Do, Youngsok Choi, Kwonho Hong
Summary: Dot1l is a key transcription factor involved in the development and function of lymphatic endothelial cells (LECs) and blood endothelial cells (BECs). Dot1l depletion and overexpression affect cell adhesion, immune response, and angiogenesis-related biological processes. Dot1l regulates specific tissue development and ion transportation through the modulation of gene expression.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Huijuan Lin, Keren Cheng, Hiroshi Kubota, Yemin Lan, Simone S. Riedel, Kazue Kakiuchi, Kotaro Sasaki, Kathrin M. Bernt, Marisa S. Bartolomei, Mengcheng Luo, P. Jeremy Wang
Summary: This study identifies the critical role of DOT1L in the self-renewal of spermatogonial stem cells, mediated by promoting the expression of fate-determining transcription factors HoxC and accumulation of H3K79me2 at specific genes.
GENES & DEVELOPMENT
(2022)
Review
Multidisciplinary Sciences
Jason H. Brickner
Summary: This article discusses the mechanisms by which histone modifications can be inherited and relates them to the phenomenon of epigenetic transcriptional memory. Recent studies have found that the histone H3 lysine 4 dimethylation associated with this memory plays a critical role in sustaining memory and can be stably maintained through multiple mitoses. This chromatin-mediated inheritance mechanism involves a physical interaction between an H3K4me2 reader, SET3C, and an H3K4me2 writer, Spp1(-) COMPASS. This is the first example of chromatin-mediated inheritance of a mark that promotes transcription.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2023)
Article
Multidisciplinary Sciences
Evelyn Chen, Enrique Lin-Shiao, Marena Trinidad, Mohammad Saffari Doost, David Colognori, Jennifer A. Doudna
Summary: The fusion of PRDM9 and Cas9 in CRISPR-Cas genome editing can increase the efficiency of homology-directed repair (HDR) and avoid off-target editing.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Zhenhui Zhong, Suhua Feng, Sascha H. Duttke, Magdalena E. Potok, Yiwei Zhang, Javier Gallego-Bartolom, Wanlu Liu, Steven E. Jacobsen
Summary: DNA methylation influences chromatin accessibility, particularly in heterochromatin, in plants. Different sequence contexts of DNA methylation interact with each other, and methylation can impact chromatin structure through mechanisms other than transcription. Increased chromatin accessibility is associated with enhanced long-range chromatin interactions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Hendrikus J. Van Heesbeen, Lars Von Oerthel, Paul M. De Vries, Cindy M. R. J. Wagemans, Marten P. Smidt
Summary: Methylation of H3K79 and its activator Dot1l may be important in brain aging and associated disorders. In aged humans, there is global hypermethylation of H3K79 in neurons, and in specific dopaminergic neurons, there is an increase in H3K79 methylation. Removing Dot1l results in a loss of H3K79 methylation and an up-regulation of respiratory chain genes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Yuan Pan, Yiman Tang, Hang Gu, Wenshu Ge
Summary: This review summarizes the effects and mechanisms of ubiquitin modification on osteogenic differentiation and highlights the latest advances in drug application in bone tissue engineering. Thorough understanding of ubiquitin modification may provide promising therapeutic targets for stem cell-based bone tissue engineering.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Junjiang Fu, Li Liao, Kyathegowdanadoddi Srinivasa Balaji, Chunli Wei, Jaehoon Kim, Jiangzhou Peng
Summary: RNF40 is an interesting new gene that plays a crucial role in cancer development, progression, and metastasis through its protein ubiquitylation activity, highlighting its important epigenetic function.
Article
Chemistry, Multidisciplinary
Haigang Song, Antony J. Burton, Sally L. Shirran, Jurate Fahrig-Kamarauskaite, Hannelore Kaspar, Tom W. Muir, Markus Kunzler, James H. Naismith
Summary: The introduction of alpha-N-methylated non-proteinogenic amino acids into peptides can enhance their biological activities. An engineered enzyme called OphMA has been shown to methylate amide bonds in non-natural amides, offering potential applications in biotechnological production of therapeutic peptides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Chemistry, Multidisciplinary
Michelle M. Mitchener, Tom W. Muir
Summary: The nucleosome, the fundamental repeating unit of chromatin, is composed of DNA wrapped around four canonical histone proteins, possessing 2-fold pseudo-symmetry that can be disrupted in cellular contexts. Post-translational modification of histones, histone removal/swapping for variants, or histone mutation may render nucleosomes asymmetric. Various techniques have been developed to investigate nucleosome asymmetry, including affinity tag-based purification, transient cross-linking strategies, synthetic biology techniques, and split intein technology. These chemical biology tools provide a means to biochemically interrogate a variety of asymmetric nucleosome species, contributing to the understanding of chromatin structure and function.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
John D. Bagert, Tom W. Muir
Summary: The field of epigenetics has rapidly expanded in the past two decades, revealing the complexity of genetic information storage and access in eukaryotes, with chemistry playing an increasingly important role. Molecular precision afforded by chemical tools is being used to establish causal biochemical relationships at the heart of epigenetic regulation.
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 90, 2021
(2021)
Article
Chemistry, Multidisciplinary
Nir Hananya, Sara K. Daley, John D. Bagert, Tom W. Muir
Summary: The study developed a efficient semi-synthesis method to create full-length ADP-ribosylated histones H3 and H2B, which were used to investigate the roles of histone ADP-ribosylation in DNA damage response. The results showed that ADP-ribosylation of serine-6 of histone H2B inhibits chromatin folding and higher-order organization, providing new insights into the impact of histone modifications on chromatin structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Aiwei Wu, Junhong Zhi, Tian Tian, Ali Cihan, Murat A. Cevher, Ziling Liu, Yael David, Tom W. Muir, Robert G. Roeder, Ming Yu
Summary: The study showed that DOT1L depletion in erythroleukemic cells does not affect the elongation rate of RNA polymerase II, but plays a significant role in transcription initiation by regulating the recruitment of transcription factor IID along with ENL. This is achieved by enhancing H2Bub1 levels and limiting the recruitment of the SAGA complex. These findings provide new insights into the role of the DOT1L complex in transcriptional regulation and its implications for MLLr leukemias.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Nazar Mashtalir, Hai T. Dao, Akshay Sankar, Hengyuan Liu, Aaron J. Corin, John D. Bagert, Eva J. Ge, Andrew R. D'Avino, Martin Filipovski, Brittany C. Michel, Geoffrey P. Dann, Tom W. Muir, Cigall Kadoch
Summary: This study identified the effects of chromatin features on mSWI/SNF activities and interactions, as well as the combinatorial contributions of complex module components, reader domains, and nucleosome engagement properties to the localization of complexes.
Review
Biochemistry & Molecular Biology
Antony J. Burton, Ghaith M. Hamza, Andrew X. Zhang, Tom W. Muir
Summary: Protein-protein interactions in the nucleus are crucial for transcriptional regulation and genomic stability, with epigenetic proteins being identified as key therapeutic targets for diseases. Recent advances in chemical biology and mass spectrometry techniques have greatly improved our understanding of histone-mediated protein interactions.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Article
Chemistry, Multidisciplinary
Hai T. Dao, Hengyuan Liu, Nazar Mashtalir, Cigall Kadoch, Tom W. Muir
Summary: This study reports a strategy for controlling the orientation of asymmetric nucleosomes and hexasomes, providing an efficient method for studying gene regulation. By using truncated DNA templates and DNA ligation, the researchers successfully prepared desymmetrized mononucleosomes and oligonucleosomes with varied DNA sequences and histone compositions. Using this technology, they investigated the impact of asymmetry on chromatin remodeling and found that cancer-associated histone mutations can cause aberrant chromatin structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Bradley J. Lukasak, Robert E. Thompson, Michelle M. Mitchener, Vanessa J. Feng, John D. Bagert, Tom W. Muir
Summary: In this study, the SpyCatcher/SpyTag system was used to assemble desymmetrized nucleoprotein complexes. This method allows for the generation of nucleosomes with asymmetric modifications and facilitates the investigation of the effects of nucleosome asymmetry on chromatin remodeling processes and histone enzyme activity.
ACS CENTRAL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Aishan Zhao, Steven P. Bodine, Qian Xie, Boyuan Wang, Geeta Ram, Richard P. Novick, Tom W. Muir
Summary: This study reveals the involvement of membrane protease regulator of agr QS (MroQ) in the production of autoinducing peptide (AIP) in Staphylococcus aureus. It also uncovers the different roles of MroQ in different agr specificity groups, enhancing our understanding of the agr response and Staphylococcus aureus virulence.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Inwha Baek, Sarah N. Le, Jongcheol Jeon, Yujin Chun, Charlotte Reed, Stephen Buratowski
Summary: Protein fusions are commonly used for fluorescence imaging and the use of small molecule dyes linked to protein tags allows for enhanced brightness and photo-stability. In order to facilitate protein fluorescent dye tagging in yeast, a modular set of vectors with various labeling protein tags and selectable markers was constructed, enabling the simultaneous observation of multiple proteins labeled with different colored dyes.
G3-GENES GENOMES GENETICS
(2022)
Article
Chemistry, Multidisciplinary
Giridhar Sekar, Adam J. Stevens, Anahita Z. Mostafavi, Pulikallu Sashi, Tom W. Muir, David Cowburn
Summary: Split intein-mediated protein trans-splicing (PTS) is a widely used method in chemical biology and biotechnology for traceless and specific protein ligation. The efficiency of PTS can be limited by external residues flanking the intein. In this study, a recently developed atypically split intein (Cat) was further modified to enhance its PTS activity in the presence of unfavorable N-extein residues. The mechanism behind the enhanced activity was explored using nuclear magnetic resonance spectroscopy and molecular dynamics simulations, highlighting the contribution of a conserved histidine residue. This enhanced extein tolerance of Cat* expands the applicability of atypically split inteins and reveals common principles of extein dependence.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Biochemistry & Molecular Biology
Michelle M. Mitchener, Tom W. Muir
Summary: Research over the past decade has revealed a new layer of epigenetic dysregulation, uncovering the association between somatic missense mutations in histones and human pathologies, especially cancer. While some of these mutations are believed to be key drivers of cancer, the effects of the majority of them on disease onset and progression are still unclear. Studies have shown that even at low dosage, histone mutants can corrupt chromatin states, providing insights into the intricate mechanisms of epigenetic control.
Review
Chemistry, Multidisciplinary
Ciaran P. Seath, Aaron D. Trowbridge, Tom W. Muir, David W. C. MacMillan
Summary: Biomolecular interactions are crucial for cellular processes, with a focus on protein-protein interactions playing a key role in cellular signaling pathways. Recent advancements in creating reactive intermediates that cross-link neighboring proteins have provided insights into the biomolecular makeup of cellular environments, accelerating the understanding of PPIs and their impact on cellular physiology.
CHEMICAL SOCIETY REVIEWS
(2021)
