Differential Gene Regulatory Network Analysis between Azacitidine-Sensitive and -Resistant Cell Lines.

Azacitidine, a DNA methylation inhibitor, is employed for the treatment of acute myeloid leukemia (AML). However, drug resistance remains a major challenge for effective azacitidine chemotherapy, though several studies have attempted to uncover the mechanisms of azacitidine resistance. With the aim to identify the mechanisms underlying acquired azacitidine resistance in cancer cell lines, we developed a computational strategy that can identify differentially regulated gene networks between drug-sensitive and -resistant cell lines by extending the existing method, differentially coexpressed gene sets (DiffCoEx). The technique specifically focuses on cell line-specific gene network analysis. We applied our method to gene networks specific to azacitidine sensitivity and identified differentially regulated gene networks between azacitidine-sensitive and -resistant cell lines. The molecular interplay between the metallothionein gene family, C19orf33, ELF3, GRB7, IL18, NRN1, and RBM47 were identified as differentially regulated gene network in drug resistant cell lines. The biological mechanisms associated with azacitidine and AML for the markers in the identified networks were verified through the literature. Our results suggest that controlling the identified genes (e.g., the metallothionein gene family) and "cellular response"-related pathways ("cellular response to zinc ion", "cellular response to copper ion", and "cellular response to cadmium ion", where the enriched functional-related genes are MT2A, MT1F, MT1G, and MT1E) may provide crucial clues to address azacitidine resistance in patients with AML. We expect that our strategy will be a useful tool to uncover patient-specific molecular interplay that provides crucial clues for precision medicine in not only gastric cancer but also complex diseases.

Genome-wide analysis of metallothionein gene family in maize to reveal its role in development and stress resistance to heavy metal.

BACKGROUND: Maize (Zea mays L.) is a widely cultivated cereal and has been used as an optimum heavy metal phytoremediation crop. Metallothionein (MT) proteins are small, cysteine-rich, proteins that play important roles in plant growth and development, and the regulation of stress response to heavy metals. However, the MT genes for maize have not been fully analyzed so far. METHODS: The putative ZmMT genes were identified by HMMER.The heat map of ZmMT genes spatial expression analysis was generated by using R with the log2 (FPKM + 1).The expression profiles of ZmMT genes under three kinds of heavy metal stresses were quantified by using qRT-PCR. The metallothionein proteins was aligned using MAFFT and phylogenetic analysis were constructed by ClustalX 2.1. The protein theoretical molecular weight and pI, subcellular localization, TFs binding sites, were predicted using ProtParam, PSORT, PlantTFDB, respectively. RESULTS: A total of 9 ZmMT genes were identified in the whole genome of maize. The results showed that eight of the nine ZmMT proteins contained one highly conserved metallothio_2 domain, while ZmMT4 contained a Metallothio_PEC domain. All the ZmMT proteins could be classified into three major groups and located on five chromosomes. The ZmMT promoters contain a large number of hormone regulatory elements and hormone-related transcription factor binding sites. The ZmMT genes exhibited spatiotemporal specific expression patterns in 23 tissues of maize development stages and showed the different expression patterns in response to Cu, Cd, and Pb heavy metal stresses. CONCLUSIONS: We identified the 9 ZmMT genes, and explored their conserved motif, tissue expression patterns, evolutionary relationship. The expression profiles of ZmMT genes under three kinds of heavy metal stresses (Cu, Cd, Pb) were analyzed. In summary, the expression of ZmMTs have poteintial to be regulated by hormones. The specific expression of ZmMTs in different tissues of maize and the response to different heavy metal stresses are revealed that the role of MT in plant growth and development, and stress resistance to heavy metals.

Genome-wide analysis of metallothionein gene family in maize to reveal its role in development and stress resistance to heavy metal

BACKGROUND: Maize (Zea mays L.) is a widely cultivated cereal and has been used as an optimum heavy metal phytoremediation crop. Metallothionein (MT) proteins are small, cysteine-rich, proteins that play important roles in plant growth and development, and the regulation of stress response to heavy metals. However, the MT genes for maize have not been fully analyzed so far. METHODS: The putative ZmMT genes were identified by HMMER. The heat map of ZmMT genes spatial expression analysis was generated by using R with the log2 (FPKM + 1). The expression profiles of ZmMT genes under three kinds of heavy metal stresses were quantified by using qRT-PCR. The metallothionein proteins was aligned using MAFFT and phylogenetic analysis were constructed by ClustalX 2.1. The protein theoretical molecular weight and pI, subcellular localization, TFs binding sites, were predicted using ProtParam, PSORT, PlantTFDB, respectively. RESULTS: A total of 9 ZmMT genes were identified in the whole genome of maize. The results showed that eight of the nine ZmMT proteins contained one highly conserved metallothio_2 domain, while ZmMT4 contained a Metallothio_PEC domain. All the ZmMT proteins could be classified into three major groups and located on five chromosomes. The ZmMT promoters contain a large number of hormone regulatory elements and hormone-related transcription factor binding sites. The ZmMT genes exhibited spatiotemporal specific expression patterns in 23 tissues of maize development stages and showed the different expression patterns in response to Cu, Cd, and Pb heavy metal stresses. CONCLUSIONS: We identified the 9 ZmMT genes, and explored their conserved motif, tissue expression patterns, evolutionary relationship. The expression profiles of ZmMT genes under three kinds of heavy metal stresses (Cu, Cd, Pb) were analyzed. In summary, the expression of ZmMTs have poteintial to be regulated by hormones. The specific expression of ZmMTs in different tissues of maize and the response to different heavy metal stresses are revealed that the role of MT in plant growth and development, and stress resistance to heavy metals.