Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell-specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c-Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug-induced downregulation of Mbd3/ NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming.
Bmi-1, the first functionally identified polycomb gene family member, plays critical roles in cell cycle regulation, cell immortalization, and cell senescence. Bmi-1 is involved in the development and progression of carcinomas and is a potent target for cancer therapy. One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16 Ink4a and p19Arf , as Bmi-1 represses the INK4a locus on which they are encoded. A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear. In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter. The BRE resided at bp ؊821 to ؊732 upstream of the p16 ATG codon. BRE alone was sufficient to allow Bmi-1-mediated regulation of the CMV promoter. Bmi-1 typically functions by forming a complex with Ring2; however, regulation of p16 was independent of Ring2. Chromatin immunoprecipitation sequencing of Bmi-1-precipitated chromatin DNA revealed that 1536 genes were targeted by Bmi-1, including genes involved in tissue-specific differentiation, cell cycle, and apoptosis. By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation. Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy.
As a critical apoptosis executioner, caspase-3 becomes activated and then enters into the nucleus to exert its function. However, the molecular mechanism of this nuclear entry of active caspase-3 is still unknown. In this study, we revealed that caspase-3 harbors a crm-1-independent nuclear export signal (NES) in its small subunit. Using reversecaspase-3 as the study model, we found that the function of the NES in caspase-3 was not disturbed by the conformational changes during induced caspase-3 activation. Mutations disrupting the cleavage activity or p3-recognition site resulted in a defect in the nuclear entry of active caspase-3. We provide evidence that the p3-mediated specific cleavage activity of active caspase-3 abrogated the function of the NES. In conclusion, our results demonstrate that during caspase-3 activation, NES is constitutively present. p3-mediated specific cleavage activity abrogates the NES function in caspase-3, thus facilitating the nuclear entry of active caspase-3.
Band selection has become a significant issue for the efficiency of hyperspectral image (HSI) processing. Although many unsupervised band selection (UBS) approaches have been developed in the last decades, a flexible and robust method is still lacking. The lack of proper understanding of the HSI data structure has resulted to the inconsistency in the outcome of UBS. Besides, most of UBS methods are either relying on complicated measurements or rather noise sensitive, which hinder the efficiency of the determined band subset. In this paper, an adaptive distance based band hierarchy (ADBH) clustering framework is proposed for unsupervised band selection in HSI, which can help to avoid the noisy bands whilst reflecting the hierarchical data structure of HSI. With a tree hierarchy-based framework, we can acquire any number of band subset. By introducing a novel adaptive distance into the hierarchy, the similarity between bands and band groups can be computed straightforward whilst reducing the effect of noisy bands. Experiments on four datasets acquired from two HSI systems have fully validated the superiority of the proposed framework.
To improve the performance of the sparse representation classification (SRC), we propose a superpixel-based feature specific sparse representation framework (SPFS-SRC) for spectral-spatial classification of hyperspectral images (HSI) at superpixel level. First, the HSI is divided into different spatial regions, each region is shape- and size-adapted and considered as a superpixel. For each superpixel, it contains a number of pixels with similar spectral characteristic. Since the utilization of multiple features in HSI classification has been proved to be an effective strategy, we have generated both spatial and spectral features for each superpixel. By assuming that all the pixels in a superpixel belongs to one certain class, a kernel SRC is introduced to the classification of HSI. In the SRC framework, we have employed a metric learning strategy to exploit the commonalities of different features. Experimental results on two popular HSI datasets have demonstrated the efficacy of our proposed methodology.
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