Article
Biology
Diana Avalos, Guillaume Rey, Diogo M. Ribeiro, Anna Ramisch, Emmanouil T. Dermitzakis, Olivier Delaneau
Summary: An analysis of cis-regulatory domains (CRDs) derived from ChIP-seq peaks and methylation data reveals cell-type specific regulatory mechanisms in immunity. Important biological mechanisms, such as cell-specific transcription factor binding sites and immune disease-associated loci, are discovered through this study. CRD-QTLs aid in interpreting GWAS findings and mapping functional regulatory units using population genomics allows the discovery of important mechanisms in gene expression regulation in immune cells. This study establishes a comprehensive resource for understanding cell-type specific regulatory mechanisms of immunity.
COMMUNICATIONS BIOLOGY
(2023)
Article
Genetics & Heredity
Julia Madsen-Osterbye, Mohamed Abdelhalim, Sarah Hazell Pickering, Philippe Collas
Summary: This study reveals that the nuclear lamina provides a repressive chromatin environment, and most genes in lamina-associated domains (LADs) are inactive. However, over ten percent of the genes in LADs are active. The study shows that the inferred enhancers of active genes in LADs can interact with other enhancers inside and outside LADs, and the distance between differentially expressed genes in LADs and distant enhancers changes during adipogenic differentiation. The involvement of lamin A/C in repressing genes in the border of an in-LAD active region within a topological domain is also shown.
Article
Genetics & Heredity
Kim Philipp Jablonski, Leopold Carron, Julien Mozziconacci, Thierry Forne, Marc-Thorsten Huett, Annick Lesne
Summary: In this study, the researchers investigated the distribution of disease-associated single-nucleotide polymorphisms (SNPs) in relation to topologically associating domains (TADs) and their borders. They found that a fraction of diseases, especially cancers, showed a preferential localization of risk loci in these genomic regions. The results suggest that genetic variations affecting the genome partitioning within TADs may contribute to the genetic risk of certain diseases, particularly cancers.
Review
Genetics & Heredity
Samuel Jianjie Yeo, Chen Ying, Melissa Jane Fullwood, Vinay Tergaonkar
Summary: This review discusses the roles of noncoding RNAs (ncRNAs) in regulating the form and function of topologically associating domains (TADs), including moderating loop extrusion through interactions with architectural proteins and facilitating TAD phase separation. The article also proposes future studies and directions to investigate these phenomena.
TRENDS IN GENETICS
(2023)
Article
Multidisciplinary Sciences
James D. Hocker, Olivier B. Poirion, Fugui Zhu, Justin Buchanan, Kai Zhang, Joshua Chiou, Tsui-Min Wang, Qingquan Zhang, Xiaomeng Hou, Yang E. Li, Yanxiao Zhang, Elie N. Farah, Allen Wang, Andrew D. McCulloch, Kyle J. Gaulton, Bing Ren, Neil C. Chi, Sebastian Preissl
Summary: This study identified cCREs in the human heart and found their associations with cardiac cell types and heart failure. It also discovered that genetic variants associated with cardiovascular diseases are enriched within these cCREs, with some potentially linked to atrial fibrillation.
Article
Multidisciplinary Sciences
Yang Eric Li, Sebastian Preissl, Xiaomeng Hou, Ziyang Zhang, Kai Zhang, Yunjiang Qiu, Olivier B. Poirion, Bin Li, Joshua Chiou, Hanqing Liu, Antonio Pinto-Duarte, Naoki Kubo, Xiaoyu Yang, Rongxin Fang, Xinxin Wang, Jee Yun Han, Jacinta Lucero, Yiming Yan, Michael Miller, Samantha Kuan, David Gorkin, Kyle J. Gaulton, Yin Shen, Michael Nunn, Eran A. Mukamel, M. Margarita Behrens, Joseph R. Ecker, Bing Ren
Summary: Recent studies have identified hundreds of neural cell types in different brain regions of mice and humans, but the transcriptional regulatory programs responsible for the unique identity and function of each cell type remain unknown. By analyzing the chromatin accessibility in individual nuclei from various brain regions, researchers have mapped candidate cis-regulatory DNA elements in distinct cell types, providing insights into the gene regulatory programs of the mammalian brain.
Article
Multidisciplinary Sciences
Niina Sandholm, Arcadio Rubio Garcia, Marcin L. Pekalski, Jamie R. J. Inshaw, Antony J. Cutler, John A. Todd
Summary: A genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) was identified, and the rs138300818 variant was found to play a role in promoting the development of early-onset T1D. Thymocyte genomic data revealed DNA sequence motifs underlying histone modifications and variants disrupting transcription factor binding motifs. The study suggests that thymic THEMIS gene expression and the rs138300818 variant contribute to the development of T1D.
SCIENTIFIC REPORTS
(2022)
Review
Biology
Ellora Hui Zhen Chua, Samen Yasar, Nathan Harmston
Summary: Enhancer skipping, a prevalent phenomenon in the genome, affects multiple types of genes. Simply assigning a genomic region to its nearest gene is problematic and a better approach is to consider both genome conservation and topological organization.
Article
Biotechnology & Applied Microbiology
Eddie Park, Yan Jiang, Lili Hao, Jingyi Hui, Yi Xing
Summary: The study suggests a mechanism where RNA editing variability can influence the phenotypes of complex traits and diseases by altering the stability and steady-state level of critical RNA molecules.
Article
Biotechnology & Applied Microbiology
Cynthia A. Kalita, Alexander Gusev
Summary: DeCAF is a new method proposed to identify cell-fraction QTLs in tumors by leveraging both allelic and total expression information. Applied to RNA-seq data from TCGA, DeCAF discovered 3664 genes with cfQTLs in 14 cell types, representing a 5.63-fold increase compared to conventional interaction-eQTL mapping.
Article
Biochemistry & Molecular Biology
Nicole Rufo, Dimitris Korovesis, Sofie Van Eygen, Rita Derua, Abhishek D. Garg, Francesca Finotello, Monica Vara-Perez, Jan Rozanc, Michael Dewaele, Peter A. de Witte, Leonidas G. Alexopoulos, Sophie Janssens, Lasse Sinkkonen, Thomas Sauter, Steven H. L. Verhelst, Patrizia Agostinis
Summary: Immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress stimulate immunomodulatory/proinflammatory factors by stressed cancer cells, with NF-kappa B/AP-1 inflammatory stress response being a key mechanism. However, the anti-inflammatory effect of IRE1 alpha kinase inhibitor KIRA6 can impact inflammation responses, urging caution in interpreting its action.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biochemistry & Molecular Biology
Anu Toropainen, Lindsey K. Stolze, Tiit Ord, Michael Whalen, Paula Marti Torrell, Verena M. Link, Minna U. Kaikkonen, Casey Romanoski
Summary: This study aims to investigate the functional consequences of noncoding SNPs in human endothelial cells (ECs) and identify likely functional SNPs through extensive experimental validation. By analyzing information from genome-wide association studies and molecular quantitative trait locus analysis, the researchers identified a set of noncoding SNPs that likely have functional effects in ECs. The study also revealed that the effects of these SNPs are context-dependent, with evidence suggesting their involvement in the risk of cardiovascular diseases at specific loci.
Article
Cell Biology
Greta Del Mistro, Shamala Riemann, Sebastian Schindler, Stefan Beissert, Roland E. Kontermann, Aurelien Ginolhac, Rashi Halder, Luana Presta, Lasse Sinkkonen, Thomas Sauter, Dagmar Kulms
Summary: Malignant melanoma (MM) is a life-threatening disease that often develops resistance to targeted kinase inhibition. In this study, the researchers found that inhibiting focal adhesion kinase (FAK) could restore sensitivity to treatment in previously resistant MM cells.
CELL DEATH & DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Anne Schedel, Ulrike Anne Friedrich, Mina N. F. Morcos, Rabea Wagener, Juha Mehtonen, Titus Watrin, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter, Asta Foersti, Arka Baksi, Maria Menzel, Peter Horak, Nagarajan Paramasivam, Grazia Fazio, Robert J. Autry, Stefan Froehling, Meinolf Suttorp, Christoph Gertzen, Holger Gohlke, Sanil Bhatia, Karin Wadt, Kjeld Schmiegelow, Martin Dugas, Daniela Richter, Hanno Glimm, Merja Heinaniemi, Rolf Jessberger, Gianni Cazzaniga, Arndt Borkhardt, Julia Hauer, Franziska Auer
Summary: Mutations in RAD21 gene in germline are associated with childhood lymphoblastic leukemia or lymphoma without CdLS phenotype.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Maleeha Maria, Negar Pouyanfar, Tiit Ord, Minna U. Kaikkonen
Summary: Genome-wide association studies have identified numerous loci associated with complex traits, and functional genomics approaches have further explored the genes regulated by these loci using bulk RNA-sequencing data. Single-cell RNA-Sequencing (scRNA-Seq) technologies have provided new opportunities for assessing gene expression changes at the single-cell level. In this review, the authors outline the methodological principles, advantages, limitations, and future considerations of single-cell eQTL studies.
Article
Oncology
Laura Oksa, Artturi Makinen, Atte Nikkila, Noora Hyvarinen, Saara Laukkanen, Anne Rokka, Pekka Haapaniemi, Masafumi Seki, Junko Takita, Otto Kauko, Merja Heinaniemi, Olli Lohi
Summary: Approximately 15-25% of acute lymphoblastic leukemias (ALL) originate from T-lineage cells, with T-ALL having a less favorable prognosis compared to B-ALL. High expression of PRMT7 was identified in T-ALL cells, and genetic deletion of PRMT7 decreased colony formation and altered arginine monomethylation patterns in protein complexes associated with RNA and DNA processing. Disruption of arginine monomethylation patterns was observed in proteins linked to T-ALL pathogenesis, such as RUNX1, leading to deregulated target gene expression. These findings suggest that PRMT7 plays a crucial role in T-ALL pathogenesis.
Review
Cell Biology
Ali Kishk, Maria Pires Pacheco, Tony Heurtaux, Lasse Sinkkonen, Jun Pang, Sabrina Fritah, Simone P. Niclou, Thomas Sauter
Summary: This review highlights the evolution of genome-scale models for neurodegenerative diseases and glioma, discussing the advantages and drawbacks of each approach and proposing improvements.
Review
Biochemistry & Molecular Biology
Tony Heurtaux, David S. Bouvier, Alexandre Benani, Sergio Helgueta Romero, Katrin B. M. Frauenknecht, Michel Mittelbronn, Lasse Sinkkonen
Summary: The translation mentions that the nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor that regulates hundreds of genes involved in various biological functions and diseases. It also highlights the importance of NRF2 activity stability in maintaining redox balance and brain homeostasis.
Article
Hematology
Mohan Babu, Durga Devi, Petri Makinen, Tiit Ord, Einari Aavik, Minna Kaikkonen, Seppo Yla-Herttuala
Summary: Diabetes is a major risk factor for peripheral arterial disease and impairs collateral remodeling and angiogenesis, but the underlying mechanisms are poorly understood. This study aimed to elucidate the cellular and molecular mechanisms of impaired post-ischemic vascular response in type 2 diabetic mice and evaluate the use of reconstituted HDL-ApoA-I nanotherapy to rescue the defect. The results showed that impaired collateral remodeling and sprouting angiogenesis in type 2 diabetic mice were associated with persistent IFN-I response in endothelial cells and macrophages. Furthermore, rHDL nanotherapy improved the impaired vascular response by reducing inflammation in endothelial cells and macrophages. Therefore, targeting persistent inflammation using rHDL nanotherapy may be a potential therapeutic strategy for type 2 diabetes-related peripheral arterial disease.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Cell Biology
Nea Korvenlaita, Mireia Gomez-Budia, Flavia Scoyni, Cristiana Pistono, Luca Giudice, Shaila Eamen, Sanna Loppi, Ana Hernandez de Sande, Benjamin Huremagic, Maria Bouvy-Liivrand, Merja Heinaniemi, Minna U. Kaikkonen, Lesley Cheng, Andrew F. Hill, Katja M. Kanninen, Guido W. Jenster, Martin E. van Royen, Laura Ramiro, Joan Montaner, Tereza Batkova, Robert Mikulik, Rosalba Giugno, Jukka Jolkkonen, Paula Korhonen, Tarja Malm
Summary: Hypoxia induces changes in the secretion of extracellular vesicles (EVs) in non-neuronal cells and pathological conditions. The secretion of miR-21-5p in EVs is increased under hypoxia. Neuronal EVs and miR-21-5p secretion may be altered under hypoxia, and miR-21-5p in EVs may serve as a potential biomarker for stroke recovery.
JOURNAL OF EXTRACELLULAR VESICLES
(2023)
Article
Biochemistry & Molecular Biology
Susanne Csader, Marsena Jasiel Ismaiah, Tiina Kuningas, Merja Heinaniemi, Janne Suhonen, Ville Mannisto, Heikki Pentikainen, Kai Savonen, Milla-Maria Tauriainen, Jean-Marie Galano, Jetty Chung-Yung Lee, Reeta Rintamaki, Piia Karisola, Hani El-Nezami, Ursula Schwab
Summary: Exercise intervention without weight loss may influence the AT morphology and fat metabolism at the gene expression level in female NAFLD subjects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Leticia Soriano-Baguet, Melanie Grusdat, Henry Kurniawan, Mohaned Benzarti, Carole Binsfeld, Anouk Ewen, Joseph Longworth, Lynn Bonetti, Luana Guerra, Davide G. Franchina, Takumi Kobayashi, Veronika Horkova, Charlene Verschueren, Sergio Helgueta, Deborah Gerard, Tushar H. More, Antonia Henne, Catherine Dostert, Sophie Farinelle, Antoine Lesur, Jean-Jacques Gerardy, Christian Jager, Michel Mittelbronn, Lasse Sinkkonen, Karsten Hiller, Johannes Meiser, Dirk Brenner
Summary: Pyruvate dehydrogenase (PDH) plays a crucial role in the metabolism and function of T helper 17 (Th17) cells. PDH is necessary for the generation of a glucose-derived citrate pool, which is essential for Th17 cell proliferation, survival, and effector function. In the absence of PDH, Th17 cells exhibit increased glutaminolysis, glycolysis, and lipid uptake, but critically low levels of cellular citrate, leading to impaired oxidative phosphorylation, lipid synthesis, and histone acetylation.
Article
Biochemistry & Molecular Biology
Jouni Harkonen, Petri Polonen, Ashik Jawahar Deen, Ilakya Selvarajan, Hanna-Riikka Teppo, Elitsa Y. Dimova, Thomas Kietzmann, Maarit Ahtiainen, Juha P. Vayrynen, Sara A. Vayrynen, Hanna Elomaa, Niko Tynkkynen, Tiia Eklund, Teijo Kuopio, Eva-Maria Talvitie, Pekka Taimen, Markku Kallajoki, Minna U. Kaikkonen, Merja Heinaniemi, Anna-Liisa Levonen
Summary: The NRF2 pathway is frequently activated in various cancer types, but a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a NRF2 activity metric and conducted a pan-cancer analysis of oncogenic NRF2 signaling using it. Our findings revealed an immunoevasive phenotype in squamous malignancies of the lung, head and neck area, cervix, and esophagus, where high NRF2 activity is associated with low interferon-gamma (IFNγ), HLA-I expression, and T cell and macrophage infiltration. These tumors have a molecular phenotype with amplification of SOX2/TP63, TP53 mutation, and CDKN2A loss, and are associated with upregulation of immunomodulatory genes NAMPT, WNT5A, SPP1, SLC7A11, SLC2A1, and PD-L1. Our functional genomics analyses suggest that these genes are candidate NRF2 targets, indicating a direct modulation of the tumor immune milieu. Single-cell mRNA data shows that cancer cells of this subtype exhibit decreased expression of IFNγ responsive ligands and increased expression of immunosuppressive ligands NAMPT, SPP1, and WNT5A involved in intercellular crosstalk. Moreover, the negative relationship between NRF2 and immune cells is explained by stromal populations of lung squamous cell carcinoma, indicating a potential effect across multiple squamous malignancies based on our molecular subtyping and deconvolution data.
Article
Cell Biology
Tamara Bintener, Maria Pires Pacheco, Demetra Philippidou, Christiane Margue, Ali Kishk, Greta Del Mistro, Luca Di Leo, Maria Moscardo Garcia, Rashi Halder, Lasse Sinkkonen, Daniela De Zio, Stephanie Kreis, Dagmar Kulms, Thomas Sauter
Summary: Despite high response rates to targeted kinase inhibitors, metastatic melanoma often relapses, calling for alternative therapies. This study used a refined workflow to predict common and melanoma-specific essential genes as potential drug targets. By reconstructing metabolic models, 28 candidate drugs were predicted and 12 showed high efficacy in vitro. Drug repurposing could expand treatment options for non-responders or those with acquired resistance to conventional melanoma treatments.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Anja Fischer, Robert Lersch, Niklas de Andrade Kraetzig, Alexander Strong, Mathias J. Friedrich, Julia Weber, Thomas Engleitner, Rupert Oellinger, Hsi-Yu Yen, Ursula Kohlhofer, Irene Gonzalez-Menendez, David Sailer, Liz Kogan, Mari Lahnalampi, Saara Laukkanen, Thorsten Kaltenbacher, Christine Klement, Majdaddin Rezaei, Tim Ammon, Juan J. Montero, Guenter Schneider, Julia Mayerle, Mathias Heikenwaelder, Marc Schmidt-Supprian, Leticia Quintanilla-Martinez, Katja Steiger, Pentao Liu, Juan Cadinanos, George S. Vassiliou, Dieter Saur, Olli Lohi, Merja Heinaeniemi, Nathalie Conte, Allan Bradley, Lena Rad, Roland Rad
Summary: Compared to the loss of tumor-suppressor function, the effects of discrete gene dysregulations caused by non-coding genome alterations are poorly understood. In this study, by perturbing the regulatory genome in mice, the researchers reveal the pervasive roles of subtle gene expression variation in cancer evolution. They identified extensive quasi-insufficiency across different tumors and discovered diverse context dependencies. The study provides important insights into tumor evolution and the tissue-specific effects of non-coding mutations.
