A Chemical Probe for the ATAD2 Bromodomain

ATAD2 is a cancer‐associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF₂ as a sulfone bio‐isostere to exploit the unique properties of fluorine, and 2) using 1,3‐interactions to control the conformation of a piperidine ring. This resulted in the first reported low‐nanomolar, selective and cell permeable chemical probe for ATAD2.     

Tetracyanoresorcin[4]arene selectively recognises trimethyllysine and inhibits its enzyme-catalysed demethylation

Abstract

Nε-methylation of lysine within proteins is a critical biological process that, among other roles, is involved in the control of gene expression. Compounds that recognise Nε-methylated lysine may therefore be useful probes for the study of the associated biological mechanisms and have therapeutic potential. Here, we show that tetracyanoresorcin[4]arene (1) selectively recognises Nε-trimethyllysine and binds to Nε-trimethyllysine within the context of a short peptide. Its binding properties compare favourably to a previously characterised Nε-trimethyllysine binder, p-sulfonatocalix[4]arene (2). We also show that both 1 and 2 inhibit the demethylation of Nε-trimethyllysine within a histone-derived peptide by the histone demethylase KDM4A.     

Epigenetic Modifications Induced by Olive Oil and Its Phenolic Compounds: A Systematic Review

Many studies demonstrated that olive oil (especially extra virgin olive oil: EVOO) phenolic compounds are bioactive molecules with anti-cancer, anti-inflammatory, anti-aging and neuroprotective activities. These effects have been recently attributed to the ability of these compounds to induce epigenetics modifications such as miRNAs expression, DNA methylation and histone modifications. In this study, we systematically review and discuss, following the PRISMA statements, the epigenetic modifications induced by EVOO and its phenols in different experimental systems. At the end of literature search through “PubMed”, “Web of Science” and “Scopus”, 43 studies were selected.Among them, 22 studies reported data on miRNAs, 15 on DNA methylation and 13 on histone modification. Most of the “epigenomic” changes observed in response to olive oil phenols’ exposure were mechanistically associated with the cancer preventive and anti-inflammatory effects. In many cases, the epigenetics effects regarding the DNA methylation were demonstrated for olive oil but without any indication regarding the presence or not of phenols. Overall, the findings of the present systematic review may have important implications for understanding the epigenetic mechanisms behind the health effects of olive oil. However, generally no direct evidence was provided for the causal relationships between epigenetics modification and EVOO health related effects. Further studies are necessary to demonstrate the real physiological consequences of the epigenetics modification induced by EVOO and its phenolic compounds.     

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

The bromodomain‐containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin‐remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone‐fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure‐based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity‐building nitro‐Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro‐Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro‐inflammatory cytokine secretion.     

Polyphenol-Enriched Blueberry Preparation Controls Breast Cancer Stem Cells by Targeting FOXO1 and miR-145

Scientific evidence supports the early deregulation of epigenetic profiles during breast carcinogenesis. Research shows that cellular transformation, carcinogenesis, and stemness maintenance are regulated by epigenetic-specific changes that involve microRNAs (miRNAs). Dietary bioactive compounds such as blueberry polyphenols may modulate susceptibility to breast cancer by the modulation of CSC survival and self-renewal pathways through the epigenetic mechanism, including the regulation of miRNA expression. Therefore, the current study aimed to assay the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on the modulation of miRNA signature and the target proteins associated with different clinical-pathological characteristics of breast cancer such as stemness, invasion, and chemoresistance using breast cancer cell lines. To this end, 4T1 and MB-MDM-231 cell lines were exposed to NBJ or PEBP for 24 h. miRNA profiling was performed in breast cancer cell cultures, and RT-qPCR was undertaken to assay the expression of target miRNA. The expression of target proteins was examined by Western blotting. Profiling of miRNA revealed that several miRNAs associated with different clinical-pathological characteristics were differentially expressed in cells treated with PEBP. The validation study showed significant downregulation of oncogenic miR-210 expression in both 4T1 and MDA-MB-231 cells exposed to PEBP. In addition, expression of tumor suppressor miR-145 was significantly increased in both cell lines treated with PEBP. Western blot analysis showed a significant increase in the relative expression of FOXO1 in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Furthermore, a significant decrease was observed in the relative expression of N-RAS in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Our data indicate a potential chemoprevention role of PEBP through the modulation of miRNA expression, particularly miR-210 and miR-145, and protection against breast cancer development and progression. Thus, PEBP may represent a source for novel chemopreventative agents against breast cancer.     

How Far Does Energy Migrate in DNA and Cause Damage? Evidence for Long‐Range Photodamage to DNA

A new DNA architecture addresses the question, how far energy migrates in DNA and forms cyclobutane pyrimidine dimers (CPDs) as photodamages causing skin cancer. The 3‐methoxyxanthone nucleoside allows site‐selective photoenergy injection into DNA. The designated CPD site lacks the phosphodiester bond and can be placed in defined distances. The CPD formation links two oligonucleotides together and allows probing by gel electrophoresis. We obtained a sigmoidal distance dependence with R₀ of 25±3 Å. Below R₀, short‐range energy migration occurs with high CPD yields and shallow distance dependence, characteristic for a coherent process. 5‐methyl‐C as epigenetic modification on the 3′‐side facilitates CPD formation. Above R₀, long‐range incoherent energy migration occurs over 30 A‐T pairs (105.4 Å). The evidence of long‐range CPD formation is fundamental for our understanding of DNA photodamaging. Open access funding enabled and organized by Projekt DEAL.     

Genomic Imprinting—The Struggle of the Genders at the Molecular Level

Genomic imprinting, the parent of origin‐dependent expression of genes, has been discovered as a fascinating example of the control of gene expression by epigenetic processes in the human body. It affects about 100 genes, which are often involved in growth and development. In this Review, we discuss the mechanisms leading to the generation of gender‐specific imprints in form of DNA methylation marks, their preservation during growth and development of the organism, and the processes that translate parental methylation marks into monoallelic gene expression. We discuss the gender‐specific dimorphic nature of imprints from an evolutionary point of view and present the prevalent model that molecular imprinting mediates a conflict of interest between the parents that occurs in viviparous animals. Finally, we summarize the relevance of parental imprinting for human health.