Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth

: Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations

Role of MicroRNA Profile Modifications in Hepatitis C Virus-Related Mixed Cryoglobulinemia

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin’s lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders

Gene regulatory network inference resources: A practical overview

Transcriptional regulation is a fundamental molecular mechanism involved in almost every aspect of life, from homeostasis to development, from metabolism to behavior, from reaction to stimuli to disease progression. In recent years, the concept of Gene Regulatory Networks (GRNs) has grown popular as an effective applied biology approach for describing the complex and highly dynamic set of transcriptional interactions, due to its easy-to-interpret features. Since cataloguing, predicting and understanding every GRN connection in all species and cellular contexts remains a great challenge for biology, researchers have developed numerous tools and methods to infer regulatory processes. In this review, we catalogue these methods in six major areas, based on the dominant underlying information leveraged to infer GRNs: Coexpression, Sequence Motifs, Chromatin Immunoprecipitation (ChIP), Orthology, Literature and Protein-Protein Interaction (PPI) specifically focused on transcriptional complexes. The methods described here cover a wide range of user-friendliness: from web tools that require no prior computational expertise to command line programs and algorithms for large scale GRN inferences. Each method for GRN inference described herein effectively illustrates a type of transcriptional relationship, with many methods being complementary to others. While a truly holistic approach for inferring and displaying GRNs remains one of the greatest challenges in the field of systems biology, we believe that the integration of multiple methods described herein provides an effective means with which experimental and computational biologists alike may obtain the most complete pictures of transcriptional relationships. This article is part of a Special Issue entitled: Transcriptional Profiles and Regulatory Gene Networks edited by Dr. Federico Manuel Giorgi and Dr. Shaun Mahony

Coronapp: A web application to annotate and monitor SARS-CoV-2 mutations

The avalanche of genomic data generated from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus requires the development of tools to detect and monitor its mutations across the world. Here, we present a webtool, coronapp, dedicated to easily processing user-provided SARS-CoV-2 genomic sequences and visualizing the current worldwide status of SARS-CoV-2 mutations. The webtool allows users to highlight mutations and categorize them by frequency, country, genomic location and effect on protein sequences, and to monitor their presence in the population over time. The tool is available at http://giorgilab.unibo.it/coronannotator/ for the annotation of user-provided sequences. The full code is freely shared at https://github.com/federicogiorgi/giorgilab/tree/master/coronannotator

Insights into the genome structure of four acetogenic bacteria with specific reference to the Wood–Ljungdahl pathway

Acetogenic bacteria are obligate anaerobes with the ability of converting carbon dioxide and other one-carbon substrates into acetate through the Wood–Ljungdahl (WL) pathway. These substrates are becoming increasingly important feedstock in industrial microbiology. The main potential industrial application of acetogenic bacteria is the production of metabolites that constitute renewable energy sources (biofuel); such bacteria are of particular interest for this purpose thanks to their low energy requirements for large-scale cultivation. Here, we report new genome sequences for four species, three of them are reported for the first time, namely Acetobacterium paludosum DSM 8237, Acetobacterium tundrae DSM 917, Acetobacterium bakii DSM 8239, and Alkalibaculum bacchi DSM 221123. We performed a comparative genomic analysis focused on the WL pathway's genes and their encoded proteins, using Acetobacterium woodii as a reference genome. The Average Nucleotide Identity (ANI) values ranged from 70% to 95% over an alignment length of 5.4–6.5 Mbp. The core genome consisted of 363 genes, whereas the number of unique genes in a single genome ranged from 486 in A. tundrae to 2360 in A.bacchi. No significant rearrangements were detected in the gene order for the Wood–Ljungdahl pathway however, two species showed variations in genes involved in formate metabolism: A. paludosum harbor two copies of fhs1, and A. bakii a truncated fdhF1. The analysis of protein networks highlighted the expansion of protein orthologues in A. woodii compared to A. bacchi, whereas protein networks involved in the WL pathway were more conserved. This study has increased our understanding on the evolution of the WL pathway in acetogenic bacteria

Histone deacetylases (HDACs): Evolution, specificity, role in transcriptional complexes, and pharmacological actionability

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