2014 Vol. 5, No. 4

Matricellular proteins: multifaceted extracellular regulators in tumor dormancy
Tiantian Wu, Gaoliang Ouyang
2014, 5(4): 249-252. doi: 10.1007/s13238-014-0023-6
Phylogenetics of varied subtypes of avian influenza viruses in China: potential threat to humans
Weifeng Shi, Wei Li, Xianbin Li, Joel Haywood, Juncai Ma, George F. Gao, Di Liu
2014, 5(4): 253-257. doi: 10.1007/s13238-014-0036-1
Homologous recombination in human embryonic stem cells using CRISPR/Cas9 nickase and a long DNA donor template
Zhili Rong, Shengyun Zhu, Yang Xu, Xuemei Fu
2014, 5(4): 258-260. doi: 10.1007/s13238-014-0032-5
Suilysin remodels the cytoskeletons of human brain microvascular endothelial cells by activating RhoA and Rac1 GTPase
Qingyu Lv, Huaijie Hao, Lili Bi, Yuling Zheng, Xuyu Zhou, Yongqiang Jiang
2014, 5(4): 261-264. doi: 10.1007/s13238-014-0037-0
Driver mutations of cancer epigenomes
David M. Roy, Logan A. Walsh, Timothy A. Chan
2014, 5(4): 265-296. doi: 10.1007/s13238-014-0031-6
Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancerassociated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
Research articles
Revisiting the TALE repeat
Dong Deng, Chuangye Yan, Jianping Wu, Xiaojing Pan, Nieng Yan
2014, 5(4): 297-306. doi: 10.1007/s13238-014-0035-2
Transcription activator-like (TAL) effectors specifically bind to double stranded (ds) DNA through a central domain of tandem repeats. Each TAL effector (TALE) repeat comprises 33-35 amino acids and recognizes one specific DNA base through a highly variable residue at a fixed position in the repeat. Structural studies have revealed the molecular basis of DNA recognition by TALE repeats. Examination of the overall structure reveals that the basic building block of TALE protein, namely a helical hairpin, is one-helix shifted from the previously defined TALE motif. Here we wish to suggest a structure-based re-demarcation of the TALE repeat which starts with the residues that bind to the DNA backbone phosphate and concludes with the base-recognition hyper-variable residue. This new numbering system is consistent with the α-solenoid superfamily to which TALE belongs, and reflects the structural integrity of TAL effectors. In addition, it confers integral number of TALE repeats that matches the number of bound DNA bases. We then present fifteen crystal structures of engineered dHax3 variants in complex with target DNA molecules, which elucidate the structural basis for the recognition of bases adenine (A) and guanine (G) by reported or uncharacterized TALE codes. Finally, we analyzed the sequence-structure correlation of the amino acid residues within a TALE repeat. The structural analyses reported here may advance the mechanistic understanding of TALE proteins and facilitate the design of TALEN with improved affinity and specificity.
The immunostimulatory effects of retinoblastoma cell supernatant on dendritic cells
Juan Ma, Huamin Han, Li Ma, Changzhen Liu, Xin Xue, Pan Ma, Xiaomei Li, Hua Tao
2014, 5(4): 307-316. doi: 10.1007/s13238-014-0029-0
Dendritic cells (DCs) are crucial for the induction and maintenance of tumor-specific immune responses. Studies have shown that tumor-associated DCs are immunosuppressed in some human tumors. However, phenotype and function of DCs in retinoblastoma (RB) remain unclear. RB cell supernatant (RBcs) was used to treat DCs in vitro to explore the effect of RB cells on DCs. DCs were generated from peripheral blood mononuclear cells of healthy donors. On day 5 of culture, DCs were treated with RBcs for 24 h, and then purified using magnetic beads. The maturation of DCs was induced by TNF-α or LPS. After treatment with RBcs, expression of co-stimulatory molecules CD80 and CD86 was elevated in DCs, accompanied by increased production of IL-12p70, TNF-α, IL-6, IL-1β, and IL-8 but decreased production of IL-10. RBcs neither inhibited DC maturation nor promoted DC apoptosis. Moreover, RBcs-exposed DCs stimulated allogenetic T cell proliferation and T cellderived cytokine production. These results indicate that RBcs can improve DCs' antigen presenting function and capability to activate T cells, suggesting that RB cells may have an immunostimulatory effect on DCs, and DCbased immunotherapy may be adopted in the treatment of RB.
A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes
Lu Sun, Yu Zhang, Bao Zhao, Mengmeng Deng, Jun Liu, Xin Li, Junwei Hou, Mingming Gui, Shuijun Zhang, Xiaodong Li, George F. Gao, Songdong Meng
2014, 5(4): 317-327. doi: 10.1007/s13238-014-0041-4
Cytotoxic T cells (CTLs) play a key role in the control of Hepatitis B virus (HBV) infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein (HBc) is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool covering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141-149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and antiHBV activity were further determined in HBV and HLAA2 transgenic mice. Finally, we show that mutations in HBc141-149 epitope are associated with viral parameters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.