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1.
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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2.
The diverse roles of SPOP in prostate cancer and kidney cancer.
Wang, Z, Song, Y, Ye, M, Dai, X, Zhu, X, Wei, W
Nature reviews. Urology. 2020;(6):339-350
Abstract
Multiple studies have confirmed that speckle-type pox virus and zinc finger (POZ) protein (SPOP) functions as a substrate adaptor of cullin 3-based E3 ligase and has a crucial role in various cellular processes via specific targeting of proteins for ubiquitination and subsequent proteasomal degradation. Dysregulation of SPOP-mediated proteolysis might be involved in the development and progression of human prostate and kidney cancers. In prostate cancer, SPOP seems to function as a tumour suppressor by targeting several proteins, including androgen receptor (AR), steroid receptor coactivator 3 (SRC3) and BRD4, for degradation, whereas it might function as an oncoprotein in kidney cancer, for example, by targeting phosphatase and tensin homologue (PTEN) for proteasomal degradation. In addition, nuclear SPOP targets AR for degradation and has a role as a tumour suppressor in prostate cancer; however, in kidney cancer, SPOP largely accumulates in the cytoplasm and fails to promote degradation of AR located in the nucleus, resulting in activation of AR-driven pathways and cancer progression. Owing to the context-dependent function of SPOP in human malignancies, further assessment of the molecular mechanisms involving SPOP in prostate and kidney cancers is needed to improve our understanding of its role in the development of these cancer types. Treatments that target SPOP might become therapeutic strategies in these malignancies in the future.
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3.
[Progress in Role of FEZF1-AS1 in Non-small Cell Lung Cancer].
Chen, J, Yin, R, Liu, X
Zhongguo fei ai za zhi = Chinese journal of lung cancer. 2020;(4):294-298
Abstract
Nowadays, accumulating evidence indicates that long non-coding RNA (lncRNA) play vital roles in tumorigenesis. As a newly discovered lncRNA, FEZ family zinc finger 1-antisense RNA 1 (FEZF1-AS1) is markedly upregulated in various malignant tumors including non-small cell lung cancer (NSCLC). Aberrant expression of FEZF1-AS1 is related to clinical characteristics of patients with NSCLC and suggests poor prognosis. Moreover, FEZF1-AS1 can regulate numerous biological processes, such as cell proliferation, migration and invasion through different mechanisms. In this article, we systematically summarize the recent research progress of FEZF1-AS1 in NSCLC, which might be a novel target for clinical therapy.
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4.
Pseudokinases: a tribble-edged sword.
Richmond, L, Keeshan, K
The FEBS journal. 2020;(19):4170-4182
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Abstract
Advances in the understanding of the Tribbles family of pseudokinases (TRIB1, TRIB2 and TRIB3) reveal these proteins as potentially valuable biomarkers of disease diagnosis, prognosis, prediction and clinical strategy. In their role as signalling mediators and scaffolding proteins, TRIBs lead to changes in protein stability and activity, which impact on diverse cellular processes such as proliferation, differentiation, cell cycle and cell death. We review the role of TRIB proteins as promising therapeutic targets, with an emphasis on their role in cancer, and as biomarkers, with potential application across diverse pathological processes.
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5.
Long noncoding RNA FEZF1-AS1 in human cancers.
Zhou, Y, Xu, S, Xia, H, Gao, Z, Huang, R, Tang, E, Jiang, X
Clinica chimica acta; international journal of clinical chemistry. 2019;:20-26
Abstract
Long noncoding RNAs (lncRNAs) have been shown to play key roles in various human tumors. Ectopic expression of the lncRNA FEZ finger zinc 1 antisense 1 (FEZF1-AS1) have been reported in different cancers, including colorectal cancer, gastric neoplasia, hepatocellular carcinoma and so on. Summarizing all literature correlated with FEZF1-AS1, it is obvious that FEZF1-AS1 is mainly involved in tumorigenesis and progression through competing endogenous RNA (ceRNA) which sponges tumor-suppressive microRNA (miRNA) and recruiting mechanism. Moreover, the aberrant expression of FEZF1-AS1 is related to clinical features of patients with cancers, and regulates cellular proliferation, anti-apoptosis, invasion and metastasis through diverse underlying mechanisms. The role of FEZF1-AS1 in carcinogenesis and progression suggests that it may be a potential diagnostic biomarker or a novel therapeutic target for cancers.
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6.
Global Regulation by CsrA and Its RNA Antagonists.
Romeo, T, Babitzke, P
Microbiology spectrum. 2018;(2)
Abstract
The sequence-specific RNA binding protein CsrA is employed by diverse bacteria in the posttranscriptional regulation of gene expression. Its binding interactions with RNA have been documented at atomic resolution and shown to alter RNA secondary structure, RNA stability, translation, and/or Rho-mediated transcription termination through a growing number of molecular mechanisms. In Gammaproteobacteria, small regulatory RNAs (sRNAs) that contain multiple CsrA binding sites compete with mRNA for binding to CsrA, thereby sequestering and antagonizing this protein. Both the synthesis and turnover of these sRNAs are regulated, allowing CsrA activity to be rapidly and efficiently adjusted in response to nutritional conditions and stresses. Feedback loops between the Csr regulatory components improve the dynamics of signal response by the Csr system. The Csr system of Escherichia coli is intimately interconnected with other global regulatory systems, permitting it to contribute to regulation by those systems. In some species, a protein antagonist of CsrA functions as part of a checkpoint for flagellum biosynthesis. In other species, a protein antagonist participates in a mechanism in which a type III secretion system is used for sensing interactions with host cells. Recent transcriptomics studies reveal vast effects of CsrA on gene expression through direct binding to hundreds of mRNAs, and indirectly through its effects on the expression of dozens of transcription factors. CsrA binding to base-pairing sRNAs and novel mRNA segments, such as the 3' untranslated region and deep within coding regions, predict its participation in yet-to-be-discovered regulatory mechanisms.
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7.
Redox Sensing by Fe2+ in Bacterial Fur Family Metalloregulators.
Pinochet-Barros, A, Helmann, JD
Antioxidants & redox signaling. 2018;(18):1858-1871
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Abstract
SIGNIFICANCE Iron is required for growth and is often redox active under cytosolic conditions. As a result of its facile redox chemistry, iron homeostasis is intricately involved with oxidative stress. Bacterial adaptation to iron limitation and oxidative stress often involves ferric uptake regulator (Fur) proteins: a diverse set of divalent cation-dependent, DNA-binding proteins that vary widely in both metal selectivity and sensitivity to metal-catalyzed oxidation. Recent Advances: Bacteria contain two Fur family metalloregulators that use ferrous iron (Fe2+) as their cofactor, Fur and PerR. Fur functions to regulate iron homeostasis in response to changes in intracellular levels of Fe2+. PerR also binds Fe2+, which enables metal-catalyzed protein oxidation as a mechanism for sensing hydrogen peroxide (H2O2). CRITICAL ISSUES To effectively regulate iron homeostasis, Fur has an Fe2+ affinity tuned to monitor the labile iron pool of the cell and may be under selective pressure to minimize iron oxidation, which would otherwise lead to an inappropriate increase in iron uptake under oxidative stress conditions. Conversely, Fe2+ is bound more tightly to PerR but exhibits high H2O2 reactivity, which enables a rapid induction of peroxide stress genes. FUTURE DIRECTIONS The features that determine the disparate reactivity of these proteins with oxidants are still poorly understood. A controlled, comparative analysis of the affinities of Fur/PerR proteins for their metal cofactors and their rate of reactivity with H2O2, combined with structure/function analyses, will be needed to define the molecular mechanisms that have facilitated this divergence of function between these two paralogous regulators.
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Microphthalmia is not a mandatory finding in X-linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu.
Kraus, C, Uebe, S, Thiel, CT, Ekici, AB, Reis, A, Zweier, C
American journal of medical genetics. Part A. 2018;(12):2872-2876
Abstract
Mutations in BCOR cause X-linked dominant and X-linked recessive forms of syndromic microphthalmia. By exome sequencing, we identified the recurrent BCOR mutation p.Pro85Leu in two brothers and their unaffected mother. While the older brother's phenotype completely fits the described phenotypic spectrum of X-linked recessive BCOR-associated Lenz microphthalmia syndrome, the younger brother showed developmental delay, microcephaly, and skeletal anomalies, but not the key feature of microphthalmia. In contrast to the previously published families, our findings demonstrate a large variability of BCOR-associated, syndromic phenotypes, indicating incomplete penetrance of p.Pro85Leu with regards to microphthalmia in males.
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TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation.
Lemattre, C, Thevenon, J, Duffourd, Y, Nambot, S, Haquet, E, Vuadelle, B, Genevieve, D, Sarda, P, Bruel, AL, Kuentz, P, et al
American journal of medical genetics. Part A. 2018;(12):2813-2818
Abstract
Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole-exome sequencing. A dominant-negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont-like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: p.Cys325Tyr and p.Tyr446His. The localization of these mutations and clinical features of Pierpont-like syndrome suggest that their functional consequences are comparable with the recurrent mutation previously described, and provided additional data to understand molecular mechanisms of TBL1XR1 anomalies.
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10.
Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome.
Carlston, CM, O'Donnell-Luria, AH, Underhill, HR, Cummings, BB, Weisburd, B, Minikel, EV, Birnbaum, DP, , , Tvrdik, T, MacArthur, DG, et al
Human mutation. 2017;(5):517-523
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Abstract
The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6-year-old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like BOS have reduced penetrance, or the misclassification of potentially pathogenic variants.