Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia.

MicroRNAs (miRNAs) have been suggested to repress transcription via binding the 3'-untranslated regions of mRNAs. However, the involvement and details of miRNA-mediated epigenetic regulation, particularly in targeting genomic DNA and mediating epigenetic regulation, remain largely uninvestigated. In the present study, transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, a clinical and highly selective drug for leukemia treatment, and contributed to bortezomib-induced cell death. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 could target CpG islands in the 5'-flanking region of the CEBPD gene. We previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for CCAAT/enhancer binding protein delta (CEBPD) gene inactivation; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. The miRNA/Ago2/YY1/PcG group protein/DNMT complex linked the inactivation of CEBPD and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Moreover, we revealed that miRNA binding is necessary for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. The present study successfully characterized the interactions of the miRNA/Ago2/YY1/PcG group protein/DNMT complex and provided new insights for miRNA-mediated epigenetic regulation in bortezomib-induced leukemic cell arrest and cell death.

Measuring interconnection of the residual cortical functional islands in persistent vegetative state and minimal conscious state with EEG nonlinear analysis.

OBJECTIVES: The aim of the study is to investigate the cortical response to painful and auditory stimuli for subjects in persistent vegetative state (PVS) and minimal conscious state (MCS), and measure the interconnection of the residual cortical functional islands with electroencephalographic (EEG) nonlinear dynamic analysis (NDA). METHODS: Thirty PVS subjects, 20 MCS subjects and 30 subjects in normal conscious state (NCS) were involved in the study. EEG was recorded under three conditions: eyes closed, auditory stimuli and painful stimuli. EEG nonlinear index of cross-approximate entropy (C-ApEn) was calculated for all subjects. RESULTS: Interconnection of local and distant cortical networks of patients in PVS was generally suppressed, and painful or auditory stimulation could hardly cause any activation of associative cortices. Instead, interconnection of local cortical networks of patients in MCS improved significantly. The only significant difference with the NCS existed in the unaffected distant cortical networks. CONCLUSIONS: Interconnection of local and distant cortical networks in MCS is superior to that of PVS. NDA could measure interconnection of the residual cortical functional islands with associative cortices in the unconscious patients. SIGNIFICANCE: NDA can characterise the interconnection of cortical networks for the unconscious state and provide some information of unconsciousness at the awareness level.

Application of nonlinear dynamics analysis in assessing unconsciousness: a preliminary study.

OBJECTIVES: To quantify the degree of unconsciousness with EEG nonlinear analysis and investigate the change of EEG nonlinear properties under different conditions. METHODS: Twenty-one subjects in persistent vegetative state (PVS), 16 in minimally conscious state (MCS) and 30 normal conscious subjects (control group) with brain trauma or stroke were involved in the study. EEG was recorded under three conditions: eyes closed, auditory stimuli and painful stimuli. EEG nonlinear indices such as Lempel-Ziv complexity (LZC), approximate entropy (ApEn) and cross-approximate entropy (cross-ApEn) were calculated for all the subjects. RESULTS: The PVS subjects had the lowest nonlinear indices followed by the MCS subjects and the control group had the highest. The PVS and MCS group had poorer response to auditory and painful stimuli than the control group. Under painful stimuli, nonlinear indices of subjects who recovered (REC) increased more significantly than non-REC subjects. CONCLUSIONS: With EEG nonlinear analysis, the degree of suppression for PVS and MCS could be quantified. The changes of brain function for unconscious subjects could be captured by EEG nonlinear analysis. SIGNIFICANCE: EEG nonlinear analysis could characterise the changes of brain function for unconscious state and might have some value in predicting prognosis of unconscious subjects.