Article
Biology
Lucy Ham, Marcel Jackson, Michael P. H. Stumpf
Summary: Single-cell expression profiling reveals extensive cell-to-cell variability at the transcriptomic and proteomic level, posing challenges in inferring dynamics and causes of variability. New mathematical models and experimental set-ups are proposed to distinguish intrinsic and extrinsic noise, providing insights into understanding the origins and effects of cell-to-cell variability.
Article
Biochemical Research Methods
Mark Jayson Cortez, Hyukpyo Hong, Boseung Choi, Jae Kyoung Kim, Kresimir Josic
Summary: This study proposes a non-Markovian, hierarchical Bayesian inference framework for quantifying the variability of cellular processes within and across cells in a population. By using a delayed birth-death process, the proposed hierarchical framework is shown to be robust and leads to improved estimates compared to its non-hierarchical counterpart when applied to in silico and experimental data. The mean delays in protein production are reported to be larger than previously thought, with a coefficient of variation of around 0.2 across the population, and not strongly correlated with protein production or growth rates.
Article
Biochemistry & Molecular Biology
Ales Varabyou, Steven L. Salzberg, Mihaela Pertea
Summary: RNA sequencing is commonly used to study gene expression, but simulations typically do not consider the impact of transcriptional noise. This study found that noise leads to systematic errors in computational methods, resulting in underestimation of transcript abundance and increased false-positive genes. Alignment-free methods may also struggle to detect transcripts expressed at low levels.
Article
Multidisciplinary Sciences
Pawel Mikulski, Philip Wolff, Tiancong Lu, Mathias Nielsen, Elsa Franco Echevarria, Danling Zhu, Julia Questa, Gerhard Saalbach, Carlo Martins, Caroline Dean
Summary: This study reveals that cold-induced silencing of Arabidopsis FLC requires the binding of VAL1 to an intronic motif. Additionally, the interacting partner complexes of VAL1, ASAP and PRC1, mediate co-transcriptional repression and chromatin modulation to effectively co-ordinate different steps in FLC silencing.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Nadezda A. Fursova, Anne H. Turberfield, Neil P. Blackledge, Emma L. Findlater, Anna Lastuvkova, Miles K. Huseyin, Paula Dobrinic, Robert J. Klose
Summary: Histone modifications play crucial roles in gene regulation and development, with little known about modifications found broadly throughout the genome. BAP1 deubiquitylase constrains H2AK119ub1 accumulation throughout the genome, impacting gene expression and transcription. Failure to constrain H2AK119ub1 compromises Polycomb complex occupancy at certain target genes, resulting in their derepression.
GENES & DEVELOPMENT
(2021)
Article
Multidisciplinary Sciences
Maelle Bellec, Jeremy Dufourt, George Hunt, Helene Lenden-Hasse, Antonio Trullo, Amal Zine El Aabidine, Marie Lamarque, Marissa M. Gaskill, Heloise Faure-Gautron, Mattias Mannervik, Melissa M. Harrison, Jean-Christophe Andrau, Cyril Favard, Ovidiu Radulescu, Mounia Lagha
Summary: Using quantitative imaging and monitoring transcription in living embryos, Bellec et al. provide evidence that the pioneer factor GAF acts as a stable mitotic bookmarker during early Drosophila development. GAF remains associated with its interphase targets during mitosis, which are bookmarked via histone acetylation. GAF binding competence for rapid activation upon mitotic exit is observed.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Sladjana Zagorac, Alex de Giorgio, Aleksandra Dabrowska, Mark Kalisz, Nuria Casas-Vila, Paul Cathcart, Angela Yiu, Silvia Ottaviani, Neta Degani, Ylenia Lombardo, Alistair Tweedie, Tracy Nissan, Keith W. Vance, Igor Ulitsky, Justin Stebbing, Leandro Castellano
Summary: The study reveals a novel lncRNA, SCIRT, that counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.
Article
Genetics & Heredity
Johannes N. Wibisana, Takehiko Inaba, Hisaaki Shinohara, Noriko Yumoto, Tetsutaro Hayashi, Mana Umeda, Masashi Ebisawa, Itoshi Nikaido, Yasushi Sako, Mariko Okada
Summary: The NF-kappa B transcription factor plays a crucial role in cell fate determination and is involved in the activation of super-enhancers. This study investigates the characteristics of NF-kappa B-mediated super-enhancer activity and suggests that NF-kappa B super-enhancers play an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions.
Article
Multidisciplinary Sciences
Andrea Ortega-Yanez, Samantha Cruz-Ruiz, Martha Vazquez, Mario Zurita
Summary: Transcription factors can activate gene expression by binding to elements near promoters or enhancers, even in heterochromatic regions. The CRISPRa system using dCas9-VPR as an artificial transcription factor was used in Drosophila to investigate its ability to activate transcription. The results showed that the CRISPRa system can activate transcription in any type of heterochromatin, but the effect on transcription depends on the intrinsic characteristics of each gene or regulatory element.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Xuxu Gou, Meenakshi Anurag, Jonathan T. Lei, Beom-Jun Kim, Purba Singh, Sinem Seker, Diana Fandino, Airi Han, Saif Rehman, Jianhong Hu, Viktoriya Korchina, Harshavardhan Doddapaneni, Lacey E. Dobrolecki, Nicholas Mitsiades, Michael T. Lewis, Alana L. Welm, Shunqiang Li, Adrian Lee, Dan R. Robinson, Charles E. Foulds, Matthew J. Ellis
Summary: Novel ESR1 gene translocations in ERα+ metastatic breast cancer were identified, some of which can promote estrogen-independent cell growth and other malignant characteristics. RNA sequencing revealed a specific gene expression pattern for functionally active ESR1 gene fusions, which was further reduced to a diagnostic 24-gene signature.
Article
Chemistry, Physical
Alena Klindziuk, Anatoly B. Kolomeisky
Summary: Transcription, a fundamental biological process, has been found to exhibit dynamic behavior of alternating between productive and inactive phases, known as transcriptional bursting. Despite significant attention from researchers, the microscopic origin and biological functions of transcriptional bursting remain unclear.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Multidisciplinary Sciences
Peter Androvic, Martina Schifferer, Katrin Perez Anderson, Ludovico Cantuti-Castelvetri, Hanyi Jiang, Hao Ji, Lu Liu, Garyfallia Gouna, Stefan A. Berghoff, Simon Besson-Girard, Johanna Knoferle, Mikael Simons, Ozgun Gokce
Summary: To understand the complexity of cellular function, the authors developed a method to combine spatially-resolved gene expression with ultrastructural morphology of single cells. They applied this method to study glial cells and T-cells in a demyelinating brain injury model in mice. The results revealed specific cell populations and correlations between gene expression and ultrastructural features in microglia.
NATURE COMMUNICATIONS
(2023)
Article
Hematology
Peng Xu, Daniel C. Scott, Beisi Xu, Yu Yao, Ruopeng Feng, Li Cheng, Kalin Mayberry, Yong-Dong Wang, Wenjian Bi, Lance E. Palmer, Moeko T. King, Hong Wang, Yuxin Li, Yiping Fan, Arno F. Alpi, Chunliang Li, Junmin Peng, James Papizan, Shondra M. Pruett-Miller, Ria Spallek, Florian Bassermann, Yong Cheng, Brenda A. Schulman, Mitchell J. Weiss
Summary: The E3 ubiquitin ligase FBXO11 relieves PRC2-mediated transcriptional repression during erythroid maturation by targeting its substrate BAHD1. Lack of FBXO11 in erythroblasts leads to developmental delay and reduced expression of maturation-associated genes. BAHD1 acts as a novel effector of PRC2-mediated repression and interacts physically with PRC2, highlighting a mechanism for eliminating PRC2 repression at developmentally poised genes during erythropoiesis.
Article
Biochemistry & Molecular Biology
Maria Douaihy, Rachel Topno, Mounia Lagha, Edouard Bertrand, Ovidiu Radulescu
Summary: Monitoring transcription in living cells reveals that it is discontinuous with active periods separated by inactive periods of distinct lifetimes. However, decoding temporal fluctuations and understanding the underlying transcriptional steps is challenging. BurstDECONV is a statistical inference method that can identify individual transcription initiation events and extract mechanistic features of transcription. Compared to alternative methods, BurstDECONV has advantages in terms of precision and flexibility, making it an ideal framework for live cell transcription imaging experiments. It is robust to noise and applicable to different biological contexts.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biotechnology & Applied Microbiology
Massimo Cavallaro, Mark D. Walsh, Matt Jones, James Teahan, Simone Tiberi, Barbel Finkenstadt, Daniel Hebenstreit
Summary: This study focuses on the contributions of processes at the 3 (' ) and 5 (' ) ends of a gene to transcriptional noise, and measures transcriptional bursting using Bayesian methodology. The results show that perturbation of polymerase shuttling typically reduces burst size, increases burst frequency, and thus limits transcriptional noise.
Article
Clinical Neurology
Ines J. de Castro, Brian Toner, Sheila Q. Xie, James Swingland, Angela Hodges, Sarah J. Tabrizi, Federico Turkheimer, Ana Pombo, Andre Khalil
Summary: The study reveals significant changes in nuclear architecture and chromosome organization in blood cells of Huntington's disease patients. These changes include increased nuclear size and filamentary shape, altered morphology of gene-rich chromosome regions, and a more centralized position of certain chromosomes. This new layer of information may contribute to understanding the mechanisms of HD and potentially facilitate blood-based HD surveillance.
NEUROLOGICAL SCIENCES
(2022)
Article
Genetics & Heredity
Dina Aljogol, I. Richard Thompson, Cameron S. Osborne, Borbala Mifsud
Summary: This article discusses multiple computational pipelines for CHi-C data analysis and compares their efficiency in identifying reproducible interactions and determining biologically significant interactions. The study finds that the optimal pipeline depends on the project-specific tolerance level for false positives and false negatives in chromatin contacts.
FRONTIERS IN GENETICS
(2022)
Article
Cell & Tissue Engineering
Shani Ben-Moshe, Tamar Veg, Rita Manco, Stav Dan, Delfina Papinutti, Aviezer Lifshitz, Aleksandra A. Kolodziejczyk, Keren Bahar Halpern, Eran Elinav, Shalev Itzkovitz
Summary: The liver has the ability to rapidly regenerate after acute damage. In this study, single-cell RNA sequencing was used to investigate the dynamics of mouse liver regeneration after acetaminophen intoxication, revealing different mechanisms involved in hepatocyte proliferation, reprogramming, and immune recruitment.
Correction
Multidisciplinary Sciences
Leviel Fluhr, Uria Mor, Aleksandra A. Kolodziejczyk, Mally Dori-Bachash, Avner Leshem, Shlomik Itav, Yotam Cohen, Jotham Suez, Niv Zmora, Claudia Moresi, Shahar Molina, Niv Ayalon, Rafael Valdes-Mas, Shanni Hornstein, Hodaya Karbi, Denise Kviatcovsky, Adi Livne, Aurelie Bukimer, Shimrit Eliyahu-Miller, Alona Metz, Alexander Brandis, Tevie Mehlman, Yael Kuperman, Michael Tsoory, Noa Stettner, Alon Harmelin, Hagit Shapiro, Eran Elinav
Article
Multidisciplinary Sciences
Eran Hodis, Elena Torlai Triglia, John Y. H. Kwon, Tommaso Biancalani, Labib R. Zakka, Saurabh Parkar, Jan-Christian Huetter, Lorenzo Buffoni, Toni M. Delorey, Devan Phillips, Danielle Dionne, Lan T. Nguyen, Denis Schapiro, Zoltan Maliga, Connor A. Jacobson, Ayal Hendel, Orit Rozenblatt-Rosen, Martin C. Mihm, Levi A. Garraway, Aviv Regev
Summary: Establishing causal relationships between genetic alterations and malignant phenotypes is challenging, but researchers have successfully connected mutant genotypes to malignant phenotypes by introducing multiple gene mutations to create genetically distinct melanoma models. The mutations also affect the tumor microenvironment and cell states.
Article
Multidisciplinary Sciences
Connor Yanchus, Kristen L. Drucker, Thomas M. Kollmeyer, Ricky Tsai, Warren Winick-Ng, Minggao Liang, Ahmad Malik, Judy Pawling, Silvana B. De Lorenzo, Asma Ali, Paul A. Decker, Matt L. Kosel, Arijit Panda, Khalid N. Al-Zahrani, Lingyan Jiang, Jared W. L. Browning, Chris Lowden, Michael Geuenich, J. Javier Hernandez, Jessica T. Gosio, Musaddeque Ahmed Section, Sampath Kumar Loganathan Paragraph, Jacob Berman, Daniel Trcka, Kulandaimanuvel Antony Michealraj, Jerome Fortin, Brittany Carson, Ethan W. Hollingsworth, Sandra Jacinto, Parisa Mazrooei, Lily Zhou, Andrew Elia, Mathieu Lupien, Housheng Hansen He, Daniel J. Murphy, Liguo Wang, Alexej Abyzov, James W. Dennis, Philipp G. Maass, Kieran Campbell, Michael D. Wilson, Daniel H. Lachance, Margaret Wrensch, John Wiencke, Tak Mak, Len A. Pennacchio, Diane E. Dickel Section Section, Axel Visel, Jeffrey Wrana, Michael D. Taylor, Gelareh Zadeh, Peter Dirks, Jeanette E. Eckel-Passow, Liliana Attisano, Ana Pombo, Cristiane M. Ida, Evgeny Z. Kvon, Robert B. Jenkins, Daniel Schramek
Summary: This study reveals the causal relationship between the single-nucleotide polymorphism rs55705857 and the increased risk of low-grade glioma (LGG). The research also identifies the molecular pathways associated with this polymorphism. The risk allele disrupts the binding of OCT2/4 and increases the expression of Myc. In a mouse model, mutating the rs55705857 locus accelerates tumor development and increases disease penetrance.
Article
Biochemistry & Molecular Biology
Shreya Mishra, Neetesh Pandey, Smriti Chawla, Madhu Sharma, Omkar Chandra, Indra Prakash Jha, Debarka SenGupta, Kedar Nath Natarajan, Vibhor Kumar
Summary: The true benefits of large single-cell transcriptome and epigenome data sets can be realized only with the development of new approaches and search tools for annotating individual cells. scEpiSearch is a tool that enables searching, comparison, and independent classification of single-cell open-chromatin profiles against a large reference of single-cell expression and open-chromatin data sets. It outperforms multiple methods in accuracy of search and low-dimensional coembedding of single-cell profiles and has unconventional utilities in revealing cell heterogeneity, multipotent behavior, and regulatory states.
Article
Biochemistry & Molecular Biology
Jong-Wan Kwon, Sang-Hyuk Seok, Somi Kim, Hyeok-Won An, Anahita Dev Choudhury, Sang-Ho Woo, Jeong-Seop Oh, Jong Kyoung Kim, Dominic C. Voon, Dae-Yong Kim, Jun Won Park
Summary: The study reveals the important role of ST2 and IL-33 in gastric cancer progression, with their expression levels clinically correlated to cancer progression. The IL-33/ST2 axis enhances the self-renewal and survival of gastric cancer stem cells, and cooperates with the canonical Wnt pathway to promote cancer stem cell activity. Inhibiting Bcl-xL can suppress the activity of the IL-33/ST2 axis, offering a novel therapeutic strategy for gastric cancer.
Article
Multidisciplinary Sciences
Lloyd Bod, Yoon-Chul Kye, Jingwen Shi, Elena Torlai Triglia, Alexandra Schnell, Johannes Fessler, Stephen M. M. Ostrowski, Max Y. Y. Von-Franque, Juhi R. R. Kuchroo, Rocky M. M. Barilla, Sarah Zaghouani, Elena Christian, Toni Marie Delorey, Kanishka Mohib, Sheng Xiao, Nadine Slingerland, Christopher J. J. Giuliano, Orr Ashenberg, Zhaorong Li, David M. M. Rothstein, David E. E. Fisher, Orit Rozenblatt-Rosen, Arlene H. H. Sharpe, Francisco J. J. Quintana, Lionel Apetoh, Aviv Regev, Vijay K. K. Kuchroo
Summary: In this study, a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice was identified. These B cells express TIM-1 and multiple co-inhibitory molecules and can enhance effector T cell responses to inhibit tumour growth.
Article
Immunology
Danping Zheng, Gayatree Mohapatra, Lara Kern, Yiming He, Merav D. Shmueli, Rafael Valdes-Mas, Aleksandra A. Kolodziejczyk, Tomasz Prochnicki, Matilde B. Vasconcelos, Lena Schorr, Franziska Hertel, Ye Seul Lee, Miguel Camacho Rufino, Emmanuelle Ceddaha, Sandy Shimshy, Ryan James Hodgetts, Mally Dori-Bachash, Christian Kleimeyer, Kim Goldenberg, Melina Heinemann, Noa Stettner, Alon Harmelin, Hagit Shapiro, Jens Puschhof, Minhu Chen, Richard A. Flavell, Eicke Latz, Yifat Merbl, Suhaib K. Abdeen, Eran Elinav
Summary: The authors demonstrate that Nlrp10 can form a functional inflammasome in vitro and ex vivo, and that it plays a protective role in dextran sodium sulfate-induced colitis in mice. Nlrp10, despite lacking a canonical leucine-rich repeat domain, is expressed in distal colonic intestinal epithelial cells (IECs) and is modulated by the intestinal microbiome.
Article
Biochemical Research Methods
Robert A. A. Beagrie, Christoph J. J. Thieme, Carlo Annunziatella, Catherine Baugher, Yingnan Zhang, Markus Schueler, Alexander Kukalev, Rieke Kempfer, Andrea M. M. Chiariello, Simona Bianco, Yichao Li, Trenton Davis, Antonio Scialdone, Lonnie R. R. Welch, Mario Nicodemi, Ana Pombo
Summary: Multiplex-genome architecture mapping (multiplex-GAM) is a faster and more affordable version of genome architecture mapping (GAM), enabling rapid, unbiased, ligation-free mapping of genome-wide chromatin interactions. A detailed comparison of multiplex-GAM and Hi-C using mouse embryonic stem cells reveals that only one-third of the strongest chromatin contacts are shared between the two methods. GAM often detects strong chromatin contacts involving 'active' regions, such as transcribed genes and super-enhancers, while Hi-C more often identifies contacts in 'inactive' regions. This highlights the need for orthogonal advances in genome-wide contact mapping technologies.
Article
Cell Biology
Mohannad Khandakji, Hind Hassan Ahmed Habish, Nawal Bakheet Salem Abdulla, Sitti Apsa Albani Kusasi, Nema Mahmoud Ghobashy Abdou, Hajer Mahmoud M. A. Al-Mulla, Reem Jawad A. A. Al Sulaiman, Salha M. Bu Jassoum, Borbala Mifsud
Summary: Identification of novel BRCA1 variants outpaces their clinical annotation, emphasizing the need for accurate computational methods for risk assessment. In this study, a BRCA1-specific machine learning model was developed to predict the pathogenicity of BRCA variants, and its performance was evaluated on different sets of variants. The model showed high accuracy in predicting pathogenicity and functional consequence, and identified potentially pathogenic variants in unreviewed BRCA1 variants.
PHYSIOLOGICAL GENOMICS
(2023)
Article
Multidisciplinary Sciences
William Villiers, Audrey Kelly, Xiaohan He, James Kaufman-Cook, Abdurrahman Elbasir, Halima Bensmail, Paul Lavender, Richard Dillon, Borbala Mifsud, Cameron S. Osborne
Summary: The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Luna Zea-Redondo, Ana Pombo
Summary: Enhancers are genomic elements that regulate gene expression in neuronal systems, playing a major role in neuronal specification, memory formation, and activity-dependent processes. They are also associated with genetic variants linked to neurological disorders. Understanding enhancer grammar is crucial for understanding gene expression programs in development and disease.
CURRENT OPINION IN SYSTEMS BIOLOGY
(2023)
Article
Oncology
Aaron Javitt, Merav D. Shmueli, Matthias P. Kramer, Aleksandra A. Kolodziejczyk, Ivan J. Cohen, Lihi Radomir, Daoud Sheban, Iris Kamer, Kevin Litchfield, Elizabeta Bab-Dinitz, Oranit Zadok, Vanessa Neiens, Adi Ulman, Hila Wolf-Levy, Avital Eisenberg-Lerner, Assaf Kacen, Michal Alon, Ana Toste Rego, Elvira Stacher-Priehse, Michael Lindner, Ina Koch, Jair Bar, Charles Swanton, Yardena Samuels, Yishai Levin, Paula C. A. da Fonseca, Eran Elinav, Nir Friedman, Silke Meiners, Yifat Merbl
Summary: Immunotherapy has significantly improved cancer treatment, but the reasons behind resistance in some patients are still not well understood. The composition of cellular proteasomes has been found to influence tumor-immune interactions and the tumor microenvironment, modulating the response to immunotherapy. By studying the degradation patterns in patient-derived non-small-cell lung carcinoma samples, the upregulation of proteasome regulator PSME4 was observed in tumors, leading to changes in proteasome activity, reduced antigenic diversity, and lack of response to immunotherapy. Therefore, precision oncology should focus on examining and targeting the heterogeneity and function of proteasome composition across different cancer types.