Shiwei Zhu

Large-scale sequencing studies discovered substantial genetic variants occurring in enhancers which regulate genes via long range chromatin interactions. Importantly, such variants could affect enhancer regulation by changing transcription factor bindings or enhancer hijacking, and in turn, make an essential contribution to disease progression. To facilitate better usage of published data and exploring enhancer deregulation in various human diseases, we created DiseaseEnhancer (http://biocc.hrbmu.edu.cn/DiseaseEnhancer/), a manually curated database for disease-associated enhancers. As of July 2017, DiseaseEnhancer includes 847 disease-associated enhancers in 143 human diseases. Database features include basic enhancer information (i.e. genomic location and target genes); disease types; associated variants on the enhancer and their mediated phenotypes (i.e. gain/loss of enhancer and the alterations of transcription factor bindings). We also include a feature on our website to export any query results into a file and download the full database. DiseaseEnhancer provides a promising avenue for researchers to facilitate the understanding of enhancer deregulation in disease pathogenesis, and identify new biomarkers for disease diagnosis and therapy.

Over the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, many of which play crucial roles in normal physiology and human disease. LncRNAs can interact with chromatin and then recruit protein complexes to remodel chromatin states, thus regulating gene expression. However, how lncRNA-chromatin interactions contribute to their biological functions is largely unknown. Here, we collected and constructed an atlas of 188,647 lncRNA-chromatin interactions in human and mouse. All lncRNAs showed diverse epigenetic modification patterns at their binding sites, especially the marks of enhancer activity. Functional analysis of lncRNA target genes further revealed that lncRNAs could exert their functions by binding to both promoter and distal regulatory elements, especially the distal regulatory elements. Intriguingly, many important pathways were observed to be widely regulated by lncRNAs through distal binding. For example, NEAT1, a cancer lncRNA, controls 13.3% of genes in the PI3K-AKT signaling pathway by interacting with distal regulatory elements. In addition, "twogene" signatures composed of a lncRNA and its distal target genes, such as HOTAIR-CRIM1, provided significant clinical benefits relative to the lncRNA alone. In summary, our findings underscored that lncRNA-distal interactions were essential for lncRNA functions, which would provide new clues to understand the molecular mechanisms of lncRNAs in complex disease.

The treatment of pancreatic cancer faces significant challenges due to connective tissue hyperplasia and severe hypoxia. Unlike oxygen-dependent Type II photosensitizers, Type I photosensitizers can produce a substantial amount of reactive oxygen species, even under hypoxic conditions, making them more suitable for photodynamic therapy of pancreatic cancer. However, the dense extracellular matrix of pancreatic cancer limits the penetration efficiency of photosensitizers, and the presence of immunosuppressive cells in the tumor microenvironment reduces the therapeutic effect. To address these challenges, we designed the photoimmunotherapeutic M1@PAP nanoparticles composed of Type I photosensitizer and anti-PD-L1 siRNA (siPD-L1), which was encapsulated into M1 macrophage membrane vesicles. In this system, pyropheophorbide-a (PPA) was covalently conjugated to poly-l-arginine (Arg9). Notably, it was capable of generating sufficient superoxide anions under hypoxic conditions, thereby functioning as a Type I photosensitizer. Furthermore, Arg9 acted as a nitric oxide (NO) donor, enhancing the penetration efficiency of the nanophotosensitizer by inhibiting cancer-associated fibroblast (CAF) activation and decomposing the tumor extracellular matrix. Additionally, M1 macrophage membrane vesicles provided active targeting capabilities and reeducated immunosuppressed M2 macrophages. The reversal of immunosuppressive microenvironment further promoted the efficacy of anti-PD-L1 siRNA immunotherapy, showing great potential in synergistic photodynamic immunotherapy against hypoxic pancreatic tumor.

Immunotherapy is showing good potential for colorectal cancer therapy, however, low responsive rates and severe immune-related drug side effects still hamper its therapeutic effectiveness. Herein, a highly stable cerasomal nano-modulator (DMC@P-Cs) with ultrasound (US)-controlled drug delivery capability for selective sonodynamic-immunotherapy is fabricated. DMC@P-Cs' lipid bilayer is self-assembled from cerasome-forming lipid (CFL), pyrophaeophorbid conjugated lipid (PL), and phospholipids containing unsaturated chemical bonds (DOPC), resulting in US-responsive lipid shell. Demethylcantharidin (DMC) as an immunotherapy adjuvant is loaded in the hydrophilic core of DMC@P-Cs. With US irradiation, reactive oxygen species (ROS) can be effectively generated from DMC@P-Cs, which can not only kill tumor cells for inducing immunogenic cell death (ICD), but also oxidize unsaturated phospholipids-DOPC to change the permeability of the lipid bilayers and facilitate controlled release of DMC, thus resulting in down-regulation of regulatory T cells (Tregs) and amplification of anti-tumor immune responses. After intravenous injection, DMC@P-Cs can efficiently accumulate at the tumor site, and local US treatment resulted in 94.73% tumor inhibition rate. In addition, there is no detectable systemic toxicity. Therefore, this study provides a highly stable and US-controllable smart delivery system to achieve synergistical sonodynamic-immunotherapy for enhanced colorectal cancer therapy.