👤 Tie-Yu Wang

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients. Show less

The task of drug-target interaction prediction holds significant importance in pharmacology and therapeutic drug design. In this paper, we present FRnet-DTI, an auto-encoder based feature manipulation and a convolutional neural network based classifier for drug target interaction prediction. Two convolutional neural networks are proposed: FRnet-Encode and FRnet-Predict. Here, one model is used for feature manipulation and the other one for classification. Using the first method FRnet-Encode, we generate 4096 features for each of the instances in each of the datasets and use the second method, FRnet-Predict, to identify interaction probability employing those features. We have tested our method on four gold standard datasets extensively used by other researchers. Experimental results shows that our method significantly improves over the state-of-the-art method on three out of four drug-target interaction gold standard datasets on both area under curve for Receiver Operating Characteristic (auROC) and area under Precision Recall curve (auPR) metric. We also introduce twenty new potential drug-target pairs for interaction based on high prediction scores. The source codes and implementation details of our methods are available from https://github.com/farshidrayhanuiu/FRnet-DTI/ and also readily available to use as an web application from http://farshidrayhan.pythonanywhere.com/FRnet-DTI/ . Show less

Oxidation of guanine generates several types of DNA lesions, such as 8-oxoguanine (8OG), 5-guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp). These guanine-derived oxidative DNA lesions interfere with both replication and transcription. However, the molecular mechanism of transcription processing of Gh and Sp remains unknown. In this study, by combining biochemical and structural analysis, we revealed distinct transcriptional processing of these chemically related oxidized lesions: 8OG allows both error-free and error-prone bypass, whereas Gh or Sp causes strong stalling and only allows slow error-prone incorporation of purines. Our structural studies provide snapshots of how polymerase II (Pol II) is stalled by a nonbulky Gh lesion in a stepwise manner, including the initial lesion encounter, ATP binding, ATP incorporation, jammed translocation, and arrested states. We show that while Gh can form hydrogen bonds with adenosine monophosphate (AMP) during incorporation, this base pair hydrogen bonding is not sufficient to hold an ATP substrate in the addition site and is not stable during Pol II translocation after the chemistry step. Intriguingly, we reveal a unique structural reconfiguration of the Gh lesion in which the hydantoin ring rotates ∼90° and is perpendicular to the upstream base pair planes. The perpendicular hydantoin ring of Gh is stabilized by noncanonical lone pair-π and CH-π interactions, as well as hydrogen bonds. As a result, the Gh lesion, as a functional mimic of a 1,2-intrastrand crosslink, occupies canonical -1 and +1 template positions and compromises the loading of the downstream template base. Furthermore, we suggest Gh and Sp lesions are potential targets of transcription-coupled repair. Show less

Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+-dependent manner. Here, we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states. Show less

Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signaling, and cell death 1 , 2 . In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU, gatekeeper MICU1 and MICU2, and an auxiliary EMRE subunit essential for Ca 2+ transport 3 – 8 . To prevent detrimental Ca 2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense the changes in cytosolic Ca 2+ concentrations to switch MCU on and off 9 , 10 . Here, we report cryo-EM structures of human mitochondrial calcium uniporter holocomplex in inhibited and Ca 2+ -activated states. These structures define the architecture of this multi-component Ca 2+ uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. This work provides a framework for understanding regulated Ca 2+ uptake in mitochondria and lends clues to modulate uniporter activity for treating mitochondrial Ca 2+ overload-related diseases. Show less

Cancer is one of the main causes of death throughout the world. The anticancer agents are indispensable for the treatment of various cancers, but most of them currently on the market are not specific, resulting in series of side effects of chemotherapy. Moreover, the emergency of drug-resistance towards cancers has already increased up to alarming level in the recent decades. Therefore, it's imperative to develop novel anticancer candidates with excellent activity against both drug-susceptible and drug-resistant cancers, and low toxicity as well. Tetrazole is the bioisoster of carboxylic acid, and its derivatives demonstrated promising anticancer activity. Hybridization of tetrazole with other anticancer pharmacophores may provide novel candidates with anticancer potency. The present review described the anticancer activity of tetrazole hybrids, and the structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of tetrazole anticancer candidates with higher efficiency. Show less

Fungi, which can cause serious infections, results in more than 1.35 million deaths annually throughout the world. Azole antifungal drugs which could inhibit the enzyme lanosterol 14α-demethylase, occupy an important position in the treatment of fungal infections. Tetrazoles, practically non-metabolized bioisosteric analog of carboxylic acid and cis-amide, possess a variety of chemotherapeutic properties, including antifungal activities. Hybridization represents a promising strategy to develop novel drugs, and hybridization of tetrazole with other antifungal pharmacophores has the potential to increase the activity and overcome the drug resistance. Various tetrazole hybrids have been designed, synthesized and screened for their antifungal activities, and some of them showed promising activity against both drug-susceptible and drug-resistant fungi. In this review, we present tetrazole hybrids for fighting against fungi. The structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of more effective candidates. Show less

Transcription, catalyzed by RNA polymerase II (Pol II) in eukaryotes, is the first step in gene expression. RNA Pol II is a 12-subunit enzyme complex regulated by many different transcription factors during transcription initiation, elongation, and termination. During elongation, Pol II encounters various types of obstacles that can cause transcriptional pausing and arrest. Through decades of research on transcriptional pausing, it is widely known that Pol II can distinguish between different types of obstacles by its active site. A major class of obstacles is DNA lesions. While some DNA lesions can cause transient transcriptional pausing, which can be bypassed by Pol II itself or with the help from other elongation factors, bulky DNA damage can cause prolonged transcriptional pausing and arrest, which signals for transcription coupled repair. Using biochemical and structural biology approaches, the outcomes of many different types of DNA lesions, DNA modifications, and DNA binding molecules to transcription were studied. In this mini review, we will describe the in vitro transcription assays with Pol II to investigate the impacts of various DNA lesions on transcriptional outcomes and the crystallization method of lesion-arrested Pol II complex. These methods can provide a general platform for the structural and biochemical analysis of Pol II transcriptional pausing and bypass mechanisms. Show less

Chemical biology generally highlights the modulation or control of life processes using chemical molecules. However, the rapid development of materials' science has resulted in the increasing application of various functional materials in biological regulation. More importantly, the state of art of creating the integration of materials, either the inorganic or organic matrices, with living organisms has opened a window of opportunity to add the multiplex function to organisms. In this review, we suggest a new concept of materials' biology that refers to promoting functional evolution of living organisms using material-based modification of structures, functions, and behaviors of biological organisms, which could change the modification of organisms from the current molecular-level regulation to materials' level. Thus, this review focuses on the recent achievements of material-based modification of organisms that evolves the biological function of cells, bacteria, and viruses using biomimetic strategies. The bioinspired strategies for material-based modification, including layer-by-layer, biomimetic mineralization, interfacial reactive deposition, etc., are briefly introduced. Furthermore, the interaction between materials and organisms has performed a broad function that is not retained by organisms at their native state, which results in the applications in structural support, protection, environment control, energy, vaccine improvement, and cancer treatment. The significance of material-based regulations of organism is to use rationally designed materials to endow new physiological functions to organisms, which provides another perspective to understand biological inorganic chemistry. The roles of materials in chemical regulations of biology are highlighted. New characteristics as well as functions can be achieved by integration the rationally designed materials onto/into living organisms, following material-assisted biological improvement/evolution. Show less

Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-Goutières Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons. Show less

Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, is broadly overexpressed by multiple tumor types and plays a vital role in tumor progression. In this study, we found that overexpression of B7-H3 effectively increased the rate of glucose consumption and lactate production, whereas knockdown of B7-H3 had the opposite effect. Furthermore, we showed that B7-H3 increased glucose consumption and lactate production by promoting hexokinase 2 (HK2) expression in CRC cells, and we also found that HK2 was a key mediator of B7-H3-induced CRC chemoresistance. Depletion of HK2 expression or treating cells with HK2 inhibitors could reverse the B7-H3-induced increase in aerobic glycolysis and B7-H3-endowed chemoresistance of cancer cells. Moreover, we verified a positive correlation between the expression of B7-H3 and HK2 in tumor tissues of CRC patients. Collectively, our findings suggest that B7-H3 may be a novel regulator of glucose metabolism and chemoresistance via controlling HK2 expression in CRC cells, a result that could help develop B7-H3 as a promising therapeutic target for CRC treatment. Show less

The three-dimensional architecture of biomolecules often creates specialized structural elements, notably short hydrogen bonds that have donor–acceptor separations below 2.7 Å. In this work, we statistically analyze 1663 high-resolution biomolecular structures from the Protein Data Bank and demonstrate that short hydrogen bonds are prevalent in proteins, protein–ligand complexes and nucleic acids. From these biological macromolecules, we characterize the preferred location, connectivity and amino acid composition in short hydrogen bonds and hydrogen bond networks, and assess their possible functional importance. Using electronic structure calculations, we further uncover how the interplay of the structural and chemical features determines the proton potential energy surfaces and proton sharing conditions in biological short hydrogen bonds. Show less