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1.
Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability.
Milazzo, G, Mercatelli, D, Di Muzio, G, Triboli, L, De Rosa, P, Perini, G, Giorgi, FM
Genes. 2020;(5)
Abstract
Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.
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2.
RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.
Phadke, R, Hedberg-Oldfors, C, Scalco, RS, Lowe, DM, Ashworth, M, Novelli, M, Vara, R, Merwick, A, Amer, H, Sofat, R, et al
Journal of inherited metabolic disease. 2020;(5):1002-1013
Abstract
In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.
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3.
Transcription factors in ferroptotic cell death.
Dai, C, Chen, X, Li, J, Comish, P, Kang, R, Tang, D
Cancer gene therapy. 2020;(9):645-656
Abstract
Ferroptosis, a form of regulated cell death, is characterized by an excessive degree of iron accumulation and lipid peroxidation. Although it was originally identified only in cells expressing a mutant RAS oncogene, ferroptosis has also been found in normal cells following treatment by small molecules (e.g., erastin and RSL3) or drugs (e.g., sulfasalazine, sorafenib, and artesunate), which target antioxidant enzyme systems, especially the amino acid antiporter system xc- and the glutathione peroxidase GPX4. Dysfunctional ferroptosis is implicated in various physiological and pathological processes (e.g., metabolism, differentiation, and immunity). Targeting the ferroptotic network appears to a new treatment option for diseases or pathological conditions (e.g., cancer, neurodegeneration, and ischemia reperfusion injury). While the molecular machinery of ferroptosis remains largely unknown, several transcription factors (e.g., TP53, NFE2L2/NRF2, ATF3, ATF4, YAP1, TAZ, TFAP2C, SP1, HIF1A, EPAS1/HIF2A, BACH1, TFEB, JUN, HIC1, and HNF4A) play multiple roles in shaping ferroptosis sensitivity through either transcription-dependent or transcription-independent mechanisms. In this review, we summarize recent progress in understanding the transcriptional regulation underlying ferroptotic cell death, and discuss how it has provided new insights into cancer therapy.
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4.
Dynamic Signatures of the Epigenome: Friend or Foe?
Machnik, M, Oleksiewicz, U
Cells. 2020;(3)
Abstract
Highly dynamic epigenetic signaling is influenced mainly by (micro)environmental stimuli and genetic factors. The exact mechanisms affecting particular epigenomic patterns differ dependently on the context. In the current review, we focus on the causes and effects of the dynamic signatures of the human epigenome as evaluated with the high-throughput profiling data and single-gene approaches. We will discuss three different aspects of phenotypic outcomes occurring as a consequence of epigenetics interplaying with genotype and environment. The first issue is related to the cases of environmental impacts on epigenetic profile, and its adverse and advantageous effects related to human health and evolutionary adaptation. The next topic will present a model of the interwoven co-evolution of genetic and epigenetic patterns exemplified with transposable elements (TEs) and their epigenetic repressors Krüppel-associated box zinc finger proteins (KRAB-ZNFs). The third aspect concentrates on the mitosis-based microevolution that takes place during carcinogenesis, leading to clonal diversity and expansion of tumor cells. The whole picture of epigenome plasticity and its role in distinct biological processes is still incomplete. However, accumulating data define epigenomic dynamics as an essential co-factor driving adaptation at the cellular and inter-species levels with a benefit or disadvantage to the host.
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5.
Transcription factors and ABC transporters: from pleiotropic drug resistance to cellular signaling in yeast.
Buechel, ER, Pinkett, HW
FEBS letters. 2020;(23):3943-3964
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Abstract
Budding yeast Saccharomyces cerevisiae survives in microenvironments utilizing networks of regulators and ATP-binding cassette (ABC) transporters to circumvent toxins and a variety of drugs. Our understanding of transcriptional regulation of ABC transporters in yeast is mainly derived from the study of multidrug resistance protein networks. Over the past two decades, this research has not only expanded the role of transcriptional regulators in pleiotropic drug resistance (PDR) but evolved to include the role that regulators play in cellular signaling and environmental adaptation. Inspection of the gene networks of the transcriptional regulators and characterization of the ABC transporters has clarified that they also contribute to environmental adaptation by controlling plasma membrane composition, toxic-metal sequestration, and oxidative stress adaptation. Additionally, ABC transporters and their regulators appear to be involved in cellular signaling for adaptation of S. cerevisiae populations to nutrient availability. In this review, we summarize the current understanding of the S. cerevisiae transcriptional regulatory networks and highlight recent work in other notable fungal organisms, underlining the expansion of the study of these gene networks across the kingdom fungi.
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6.
How Hormones and MADS-Box Transcription Factors Are Involved in Controlling Fruit Set and Parthenocarpy in Tomato.
Molesini, B, Dusi, V, Pennisi, F, Pandolfini, T
Genes. 2020;(12)
Abstract
Fruit set is the earliest phase of fruit growth and represents the onset of ovary growth after successful fertilization. In parthenocarpy, fruit formation is less affected by environmental factors because it occurs in the absence of pollination and fertilization, making parthenocarpy a highly desired agronomic trait. Elucidating the genetic program controlling parthenocarpy, and more generally fruit set, may have important implications in agriculture, considering the need for crops to be adaptable to climate changes. Several phytohormones play an important role in the transition from flower to fruit. Further complexity emerges from functional analysis of floral homeotic genes. Some homeotic MADS-box genes are implicated in fruit growth and development, displaying an expression pattern commonly observed for ovary growth repressors. Here, we provide an overview of recent discoveries on the molecular regulatory gene network underlying fruit set in tomato, the model organism for fleshy fruit development due to the many genetic and genomic resources available. We describe how the genetic modification of components of this network can cause parthenocarpy, discussing the contribution of hormonal signals and MADS-box transcription factors.
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7.
TRIM25 and its emerging RNA-binding roles in antiviral defense.
Choudhury, NR, Heikel, G, Michlewski, G
Wiley interdisciplinary reviews. RNA. 2020;(4):e1588
Abstract
The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how TRIM25 binding to RNA could modulate its functions and play part in the antiviral response. These findings have opened new lines of investigations into functional and molecular roles of TRIM25 and other E3 ubiquitin ligases in cell biology and control of pathogenic infections. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition.
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8.
LAG-3: from molecular functions to clinical applications.
Maruhashi, T, Sugiura, D, Okazaki, IM, Okazaki, T
Journal for immunotherapy of cancer. 2020;(2)
Abstract
To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.
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9.
An update and perspectives on the use of promoters in plant genetic engineering.
Kummari, D, Palakolanu, SR, Kishor, PBK, Bhatnagar-Mathur, P, Singam, P, Vadez, V, Sharma, KK
Journal of biosciences. 2020
Abstract
Genetically engineered plants have varied applications in agriculture for enhancing the values of food and feed. Genetic engineering aims to introduce selected genetic regions with desirable traits into target plants for both spatial and temporal expressions. Promoters are the key elements responsible for regulating gene expressions by modulating the transcription factors (TFs) through recognition of RNA polymerases. Based on their recognition and expression, RNA polymerases were categorized into RNA pol II and pol III promoters. Promoter activity and specificity are the two prime parameters in regulating the transgene expression. Since the use of constitutive promoters like Cauliflower mosaic virus (CaMV) 35S may lead to adverse effects on nontarget organisms or ecosystem, inducible/tissue specific promoters and/or the RNA pol III promoters provide myriad opportunities for gene expressions with controlled regulation and with minimum adverse effects. Besides their role in transgene expression, their influence in synthetic biology and genome editing are also discussed. This review provides an update on the importance, current prospects, and insight into the advantages and disadvantages of promoters reported thus far would help to utilize them in the endeavour to develop nutritionally and agronomically improved transgenic crops for commercialization.
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10.
Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20.
Juven, A, Nambot, S, Piton, A, Jean-Marçais, N, Masurel, A, Callier, P, Marle, N, Mosca-Boidron, AL, Kuentz, P, Philippe, C, et al
European journal of human genetics : EJHG. 2020;(8):1044-1055
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Abstract
Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.