Review
Pharmacology & Pharmacy
Stephin Baby, Durgesh Gurukkala Valapil, Nagula Shankaraiah
Summary: Epigenetic enzyme-targeted therapy is a promising development in drug discovery, with histone deacetylases and DNA methyltransferases being investigated as druggable targets. Recently, histone methyltransferases and lysine demethylase inhibitors have become the focus of clinical trials as potential epi-drugs. KDM4 enzymes, part of the 2-OG-dependent oxygenases group, have attracted attention as novel targets in cancer therapy, with efforts being made to develop selective small molecule inhibitors.
DRUG DISCOVERY TODAY
(2021)
Review
Oncology
Benluvankar Varghese, Nunzio Del Gaudio, Gilda Cobellis, Lucia Altucci, Angela Nebbioso
Summary: Breast cancer is the second leading cause of cancer death in women, with genetic mutations and epigenetic modifications playing a critical role in its progression. The KDM4 enzymes are considered potential therapeutic targets for breast cancer, but the lack of selective inhibitors has hindered their entry into clinical trials.
FRONTIERS IN ONCOLOGY
(2021)
Article
Cell Biology
Baoyu Chen, Yuwen Zhu, Junliang Chen, Yifei Feng, Yong Xu
Summary: This study reveals that differential TCL expression in malignant colorectal cancer cells is associated with histone H3K9 methylation, and the lysine demethylase KDM4B is essential for TCL transcription. KDM4B interacts with the transcription factor ERG1 to activate TCL transcription by facilitating the assembly of pre-initiation complex on the TCL promoter, ultimately influencing migration and invasion of CRC cells. Additionally, upregulation of KDM4B in advanced stage CRC specimens suggests it may serve as a potential therapeutic target for CRC intervention.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Baoyu Chen, Wenhui Dong, Tinghui Shao, Xiulian Miao, Yan Guo, Xingyu Liu, Yifei Feng
Summary: The KDM4-DBC1-SIRT1 pathway was found to regulate EMT and contribute to the development of intestinal fibrosis. Depletion or inhibition of KDM4A attenuated TGF-beta induced EMT and normalized SIRT1 activity. Therefore, targeting this pathway may be a potential strategy for treating intestinal fibrosis in IBDs.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Michael J. Hitchler, Frederick E. Domann
Summary: The development of multicellular organisms involves a complex genetic program controlled by an epigenetic state, with inputs affecting changes in the epigenetic landscape remaining unknown. Dynamic changes in cellular metabolism, redox, free radical production, and oxygen availability are associated with development, impacting gene expression. Oxygen, metabolism, and reactive oxygen species influence redox signaling to limit key epigenetic cofactors, suggesting a close relationship between these factors and epigenetic marks.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Microbiology
H. Martin Kramer, Michael F. Seidl, Bart P. H. J. Thomma, David E. Cook
Summary: Analyzing the H3K27me3 and transcription data of the plant-pathogenic fungus Verticillium dahliae grown in three in vitro cultivation media, it was found that many H3K27me3 domains displayed stable profiles across different conditions, while some differentially transcribed genes were associated with local quantitative differences in H3K27me3 ChIP-seq signals. This suggests that while H3K27me3 may play a role in transcriptional variation, it is not a universal regulator of differential transcription in response to environmental cues.
Article
Cell Biology
Shivendra Singh, Ahmed Abu-Zaid, Hongjian Jin, Jie Fang, Qiong Wu, Tingting Wang, Helin Feng, Waise Quarni, Ying Shao, Lily Maxham, Alireza Abdolvahabi, Mi-Kyung Yun, Sivaraja Vaithiyalingam, Haiyan Tan, John Bowling, Victoria Honnell, Brandon Young, Yian Guo, Richa Bajpai, Shondra M. Pruett-Miller, Gerard C. Grosveld, Mark Hatley, Beisi Xu, Yiping Fan, Gang Wu, Eleanor Y. Chen, Taosheng Chen, Peter W. Lewis, Zoran Rankovic, Yimei Li, Andrew J. Murphy, John Easton, Junmin Peng, Xiang Chen, Ruoning Wang, Stephen W. White, Andrew M. Davidoff, Jun Yang
Summary: This study identifies KDM4B as a therapeutic vulnerability for PAX3-FOXO1(+) RMS. Inhibition of KDM4B delays tumor growth and suppresses the expression of core oncogenic transcription factors, causing epigenetic alterations of PAX3-FOXO1-governed superenhancers.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Genetics & Heredity
Jessica Connacher, Gabrielle A. Josling, Lindsey M. Orchard, Janette Reader, Manuel Llinas, Lyn-Marie Birkholtz
Summary: In this study, the researchers identified a stage-specific association between repressive histone modifications (H3K36me2&3) and transcriptional reprogramming in Plasmodium falciparum early sexual development. They found that H3K36me2&3 are associated with the repression of genes involved in asexual proliferation and sexual commitment, essential for the transition from early gametocyte differentiation to intermediate development. Additionally, the study showed that the transcription factor AP2-G, a master regulator of commitment, is actively repressed in stage II gametocytes.
EPIGENETICS & CHROMATIN
(2021)
Review
Plant Sciences
Mu Xiao, Jinbiao Wang, Fang Xu
Summary: Plants dynamically regulate their gene expression in response to challenging environments through histone methylation. Osmotic stress can cause significant changes in histone methylation profiles and genome-wide transcriptional reprogramming. However, the precise mechanism of how stress-inducible genes are epigenetically regulated by histone methylation remains largely unknown. This review summarizes recent findings on the interaction between histone (de)methylation and osmotic stress, focusing on the effects of stress on histone methylation profiles and how histone methylation optimizes plant performance under stress conditions.
FRONTIERS IN PLANT SCIENCE
(2022)
Review
Genetics & Heredity
Egor Pavlenko, Till Ruengeler, Paulina Engel, Simon Poepsel
Summary: This article reviews the function of KDM5 family histone demethylases and their interactions with other molecules, highlighting the questions that need to be addressed. Understanding the regulation of KDM5 proteins in chromatin is an important step in understanding histone demethylation.
FRONTIERS IN GENETICS
(2022)
Review
Plant Sciences
Diego Ornelas-Ayala, Carlos Cortes-Quinones, Jose Olvera-Herrera, Berenice Garcia-Ponce, Adriana Garay-Arroyo, Elena R. Alvarez-Buylla, Maria de la Paz Sanchez
Summary: The Trithorax Group (TrxG) is a conserved complex that regulates transcriptional activation in plants. Recent research has identified new TrxG components and interactions, highlighting their importance in specific tissues.
Article
Multidisciplinary Sciences
Debosmita Sardar, Hsiao-Chi Chen, Amanda Reyes, Srinidhi Varadharajan, Antrix Jain, Carrie Mohila, Rachel Curry, Brittney Lozzi, Kavitha Rajendran, Alexis Cervantes, Kwanha Yu, Ali Jalali, Ganesh Rao, Stephen C. Mack, Benjamin Deneen
Summary: Epigenetic dysregulation is a common characteristic of cancer, leading to altered gene expression patterns that drive malignancy. This study reveals that the developmental transcription factor Sox9 plays different roles in high-grade glioma and ependymoma, possibly due to its interactions with different proteins and fusion events. The study also demonstrates the functional synergy between Sox9 and ZR(FUS) in promoting ependymoma tumorigenesis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Plant Sciences
Qiang Han, Yu-Hung Hung, Changqing Zhang, Arthur Bartels, Matthew Rea, Hanwen Yang, Christine Park, Xiang-Qian Zhang, Robert L. L. Fischer, Wenyan Xiao, Tzung-Fu Hsieh
Summary: In Arabidopsis, the maternal linker histone H1 influences DME-mediated demethylation, but has limited effects on gene transcription and overall imprinting regulation in the endosperm.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Yang Sun, Yan Teng, Liyuan Wang, Zhaoying Zhang, ChaoJia Chen, Yingchun Wang, Xiaodong Zhang, Peng Xiang, Xiaojia Song, Jinghui Lu, Nailin Li, Lifen Gao, Xiaohong Liang, Yuchen Xia, Zhuanchang Wu, Chunhong Ma
Summary: This study identifies LINC01431 as a novel host restriction factor for HBV transcription. It competitively binds with PRMT1 to inhibit the ubiquitination and degradation of PRMT1 mediated by HBx, thus repressing cccDNA transcription. In turn, HBV transcriptionally suppresses LINC01431 expression by inhibiting the transcription factor ZHX2.
Review
Gastroenterology & Hepatology
Xing-Yu Liu, Chuan-Hao Guo, Zhi-Yuan Xi, Xin-Qi Xu, Qing-Yang Zhao, Li-Sha Li, Ying Wang
Summary: In pancreatic cancer research, histone methylation plays a crucial role, with writers and erasers potentially serving as therapeutic targets, while further research on reader domains is needed.
WORLD JOURNAL OF GASTROENTEROLOGY
(2021)
Article
Cell & Tissue Engineering
Wei Gu, Hua Wang, Xiaofeng Huang, Judith Kraiczy, Pratik N. P. Singh, Charles Ng, Sezin Dagdeviren, Sean Houghton, Oscar Pellon-Cardenas, Ying Lan, Yaohui Nie, Jiaoyue Zhang, Kushal K. Banerjee, Emily J. Onufer, Brad W. Warner, Jason Spence, Ellen Scherl, Shahin Rafii, Richard T. Lee, Michael P. Verzi, David Redmond, Randy Longman, Kristian Helin, Ramesh A. Shivdasani, Qiao Zhou
Summary: SATB2 plays a crucial role in maintaining the identity of adult colonic stem cells and epithelial cells in mice and humans.
Article
Biochemistry & Molecular Biology
Dawei Huo, Zhaowei Yu, Rui Li, Meihan Gong, Simone Sidoli, Xukun Lu, Yuying Hou, Zhongye Dai, Yu Kong, Guifen Liu, Ole N. Jensen, Wei Xie, Kristian Helin, Chaoyang Xiong, Guohong Li, Yong Zhang, Xudong Wu
Summary: This study reveals the dynamic chromatin configuration of CGIs during exit from naive pluripotency and provides a conceptual framework for the spatiotemporal establishment of PcG functions.
Article
Biology
Morteza Chalabi Hajkarim, Ella Karjalainen, Mikhail Osipovitch, Konstantinos Dimopoulos, Sandra L. Gordon, Francesca Ambri, Kasper Dindler Rasmussen, Kirsten Gronbaek, Kristian Helin, Krister Wennerberg, Kyoung-Jae Won
Summary: In this article, the authors introduce a toolkit called compaRe for large-scale multiparameter data analysis. The toolkit integrates quality control, data bias correction, and data visualization methods, and provides faster and more reliable analysis results through a mass-aware gridding algorithm-based similarity analysis. The results show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles, as well as identify multiple types of phenotypic response patterns in drug response data.
Article
Biology
Xiaokang Wang, Wojciech Rosikiewicz, Yurii Sedkov, Tanner Martinez, Baranda S. Hansen, Patrick Schreiner, Jesper Christensen, Beisi Xu, Shondra M. Pruett-Miller, Kristian Helin, Hans-Martin Herz
Summary: This study identifies PROSER1 as a regulator of TET2 O-GlcNAcylation and its role in DNA demethylation. PROSER1 mediates the interaction between OGT and TET2, promoting TET2 O-GlcNAcylation and protein stability. Furthermore, PROSER1 colocalizes with UTX, TET1/2, and OGT on many genomic elements, suggesting its involvement in regulating chromatin-associated proteins via OGT-mediated O-GlcNAcylation.
LIFE SCIENCE ALLIANCE
(2022)
Review
Biochemistry & Molecular Biology
Leandro Simonetti, Jakob Nilsson, Gerald McInerney, Ylva Ivarsson, Norman E. Davey
Summary: SLiM-mediated interactions provide an unique strategy for viral intervention by mimicry of host SLiMs. Targeting commonly mimicked SLiMs could broaden the spectrum of antiviral drugs and improve our ability to handle viral outbreaks. In this opinion article, we advocate the therapeutic relevance of SLiMs as targets for broad-spectrum antiviral inhibitors.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E. Davey, Ylva Ivarsson
Summary: Phosphorylation is a common post-translation modification that regulates protein function through protein-protein interactions. We created a phosphomimetic peptide-phage display library to discover phosphosites that modulate short linear motif-based interactions. Our research identified 248 phosphosites that modulate motif-mediated interactions, and we studied the phospho-dependent interaction between clathrin and HURP in detail. The structural characterization of the clathrin-HURP complex revealed the molecular basis for the phospho-dependency. Our work demonstrates the importance of phosphomimetic ProP-PD in discovering novel phospho-modulated interactions essential for cellular function.
MOLECULAR SYSTEMS BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Hua Wang, Zheng Fan, Pavel V. Shliaha, Matthew Miele, Ronald C. Hendrickson, Xuejun Jiang, Kristian Helin
Summary: Using mouse embryonic stem cells, we found that acute ablation of shared subunits of the SET1/COMPASS complexes leads to a complete loss of all H3K4 methylation. H3K4me3 turnover is faster than H3K4me1 and H3K4me2, and it relies on KDM5 demethylases. Acute loss of H3K4me3 does not affect transcriptional initiation but results in decreased transcriptional output, increased RNAPII pausing, and slower elongation.
Correction
Multidisciplinary Sciences
Hua Wang, Zheng Fan, Pavel V. Shliaha, Matthew Miele, Ronald C. Hendrickson, Xuejun Jiang, Kristian Helin
News Item
Genetics & Heredity
Chang Huang, Kristian Helin
Summary: New research suggests that histone H2B N terminus multisite lysine acetylation (H2BNTac) is a significant characteristic of active enhancers and could greatly enhance enhancer prediction accuracy.
Article
Biochemistry & Molecular Biology
Zhen Sun, Yuan Lin, Mohammed T. Islam, Richard Koche, Lin Hedehus, Dingyu Liu, Chang Huang, Thomas Vierbuchen, Charles L. Sawyers, Kristian Helin
Summary: Nuclear receptor-binding SET-domain protein 1 (NSD1) is a crucial methyltransferase involved in transcriptional regulation and is dysregulated in diseases like Sotos syndrome. NSD1 associates with H3K36me2 at regulatory elements, particularly enhancers. It promotes enhancer-dependent gene transcription by facilitating RNA polymerase II pause release, affecting cell fate transition and Sotos syndrome development.
Article
Biochemistry & Molecular Biology
Emil P. T. Hertz, Ignacio Alonso-de Vega, Thomas Kruse, Yiqing Wang, Ivo A. Hendriks, Anna H. Bizard, Ania Eugui-Anta, Ronald T. Hay, Michael L. Nielsen, Jakob Nilsson, Ian D. Hickson, Niels Mailand
Summary: Hertz et al. use CRISPR screening to identify genetic vulnerabilities to inhibition of SUMOylation in human cells. They show that SUMO exerts its essential role in cell proliferation via NIP45- and BTRR-PICH-mediated DNA catenane resolution pathways. NIP45 mediates a TOP2-independent DNA catenane resolution process through its SUMO-like domains, promoting SUMOylation of specific factors including the SLX4 multi-nuclease complex, which contributes to catenane conversion into DSBs. Their findings establish the importance of SUMOylation in enabling resolution of toxic DNA catenanes via non-epistatic NIP45- and BTRR-PICH-dependent pathways to prevent mitotic failure.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Stine L. Hansen, Hjalte L. Larsen, Laura M. Pikkupeura, Grzegorz Maciag, Jordi Guiu, Iris Muller, Ditte L. Clement, Christina Mueller, Jens Vilstrup Johansen, Kristian Helin, Mads Lerdrup, Kim B. Jensen
Summary: By studying mouse fetal and adult small intestinal organoids, it was found that rare adult-like cells exist in fetal organoids, suggesting that fetal organoids have the potential to mature but are regulated by certain factors. Through a CRISPR-Cas9 screen, Smarca4 and Smarcc1 were identified as important factors for maintaining the immature progenitor state. This study demonstrates the usefulness of organoid models in identifying factors regulating cell fate and state transitions during tissue maturation and reveals the role of SMARCA4 and SMARCC1 in preventing precocious differentiation during intestinal development.
Editorial Material
Oncology
Helene Damhofer, Kristian Helin
Summary: The dense desmoplastic stroma in pancreatic cancer hinders successful immune-mediated tumor control. Recent research shows that inhibiting EZH2 can relieve the suppressive effect of tumor stroma, allowing for increased expression of pro-inflammatory chemokines after therapy-induced senescence. This boost in NK and T cell recruitment enhances immunological tumor control.
Article
Biochemistry & Molecular Biology
Aliaksandra Radzisheuskaya, Isabel Pena-Romer, Eugenia Lorenzini, Richard Koche, Yingqian Zhan, Pavel Shliaha, Alexandra J. Cooper, Zheng Fan, Daria Shlyueva, Jens Johansen, Ronald C. Hendrickson, Kristian Helin
Summary: This study identified the nucleosome-remodeling factor BPTF as a crucial regulator for the survival of AML cells. BPTF forms a complex with other proteins that remodels the chromatin structure in leukemia cells and maintains the normal gene expression program. The study also found that specific chromatin reader domains in BPTF are dispensable for the growth of leukemia cells.
