Genetic and selective constraints on the optimization of gene product diversity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 22, 2024

RNA and protein expressed from the same gene can have diverse isoforms due to various post-transcriptional post-translational modifications. For vast majority of alternative isoforms, It is unknown whether they are adaptive or simply biological noise. As we cannot experimentally probe function each isoform, ask distribution across genes species consistent with expectations different evolutionary processes. However, there currently no theoretical framework that generate such predictions. To address this, developed a mathematical model where isoform abundances determined collectively by

Язык: Английский

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The Role of ISG15 in Cancer Biology: Systematic Evaluation of ISG15 Expression and Its Molecular Interactions in a Pan-Cancer Context

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 21, 2024

Abstract ISG15’s dual role in cancer biology still remains unclear. One major area requiring further investigation is the molecular mechanisms underlying pro- and anti-tumorigenic roles different types. In this study, we try to find probable pathways that could be influenced by ISG15 cancers. ISG15, a ubiquitin-like protein essential post-translational modification ISGylation, which involves series of E1, E2, E3 enzymes. During viral infections, stimulates Type I interferon production affects key proteins such as STAT1, JAK-1, MDA-5, Mx1, RIG-1, thus impacting both host immunity evasion strategies. Furthermore, exhibits complex cancer, acting either tumor suppressor or an oncogene depending on its state—free conjugated. Intracellular free stability, while extracellular has immunomodulatory effects. Despite significant immune regulation biology, exact through influences progression remain fully elucidated. examined development across 22 types integrating data from high-throughput databases including TCGA, GTEx, CPTAC. We evaluated expression at mRNA levels, noting increased all except Kidney Chromophobe (KICH) elevated levels nine out ten analyzed types, with exception liver carcinoma. Analysis TP53 mutations showed reduced KICH regardless mutation status. Correlation analyses identified seven highly correlated genes—IFI35, IFI44, OASL, MX1, RSAD2, OAS2, IRF7 involved downstream signaling. Protein-protein interaction networks revealed hub genes IFIT1, IFIT2, are crucial pathogenesis warrant in-depth studies for therapeutic targets drug repurposing.

Язык: Английский

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The emergence and evolution of gene expression in genome regions replete with regulatory motifs

Опубликована: Дек. 5, 2024

Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of DNA, also create new a process called emergence. Non-regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires stretch promoter, contains two -10 -35 boxes. However, these occur in both promoters non-promoter multiple copies. They have been implicated some studies improve promoter activity, others repress it. Here, we ask whether presence such different genetic sequences influences evolution To understand how influence emergence evolution, start from 50 “promoter islands”, enriched with We mutagenize starting “parent” sequences, measure driven 240’000 resulting mutants. find that probability mutations an active varies more than 200-fold, not correlated number motifs. For parent without created over 1’500 boxes at unique positions library, but only ∼0.3% resulted de-novo activity. Only ∼13% all contribute 11 specific partially overlap preexisting ones modulate expression. do Overall, our work demonstrates evolution. It has implications predicting understanding genes, phenotypic

Язык: Английский

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Prion protein regulates invasiveness in glioblastoma stem cells

BMC Cancer, Год журнала: 2024, Номер 24(1)

Опубликована: Дек. 18, 2024

Glioblastoma (GBM) is an aggressive brain tumor driven by glioblastoma stem cells (GSCs), which represent appealing target for therapeutic interventions. The cellular prion protein (PrPC), a scaffold involved in diverse processes, interacts with various membrane and extracellular matrix molecules, influencing biology. Herein, we investigate the impact of PrPC expression on GBM. To address this goal, employed CRISPR-Cas9 technology to generate knockout (KO) cell lines, enabling detailed loss-of-function studies. Bulk RNA sequencing followed differentially expressed gene pathway enrichment analyses between U87 or U251 PrPC-wild-type (WT) PrPC-knockout were used identify pathways regulated PrPC. Immunofluorescence assays evaluate morphology distribution. For assessment levels, Western blot flow cytometry employed. Transwell growth curve determine loss-of-PrPC GBM invasiveness proliferation, respectively. Single-cell analysis data from patient tumors Cancer Genome Atlas (TCGA) Broad Institute Single-Cell Data Portal correspondence our vitro results samples. Transcriptome PrPC-KO lines revealed altered genes associated crucial progression pathways, including migration, stemness. These findings corroborated that impaired invasion, self-renewal cells, highlighting its critical role sustaining growth. Notably, disrupted localization key stemness markers, particularly CD44. Additionally, modulation levels through CD44 overexpression further emphasizes their regulatory these processes. establish as modulator essential molecules surface GSCs, potential

Язык: Английский

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The emergence and evolution of gene expression in genome regions replete with regulatory motifs

eLife, Год журнала: 2024, Номер 13

Опубликована: Дек. 20, 2024

Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of DNA, also create new a process called emergence. Non-regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires stretch promoter, contains two –10 –35 boxes. However, these occur in both promoters non-promoter multiple copies. They have been implicated some studies improve promoter activity, others repress it. Here, we ask whether presence such different genetic sequences influences evolution To understand how influence emergence evolution, start from 50 ‘promoter islands’, enriched with We mutagenize starting ‘parent’ sequences, measure driven 240,000 resulting mutants. find that probability mutations an active varies more than 200-fold, not correlated number motifs. For parent without created over 1500 boxes at unique positions library, but only ~0.3% resulted de-novo activity. Only ~13% all contribute 11 specific partially overlap preexisting ones modulate expression. do Overall, our work demonstrates evolution. It has implications predicting understanding de novo genes, phenotypic

Язык: Английский

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