Publications by authors named "Chunjiang He"

41 Publications

YTHDF1 promotes mRNA degradation via YTHDF1-AGO2 interaction and phase separation.

Cell Prolif 2021 Nov 25:e13157. Epub 2021 Nov 25.

School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Objectives: YTHDF1 is known as a m A reader protein, and many researches of YTHDF1 focused on the regulation of mRNA translation efficiency. However, YTHDF1 is also related to RNA degradation, but how YTHDF1 regulates mRNA degradation is indefinite. Liquid-liquid phase separation (LLPS) underlies the formation of membraneless compartments in mammal cells, and there are few reports focused on the correlation of RNA degradation with LLPS. In this research, we focused on the mechanism of YTHDF1 degraded mRNA through LLPS.

Materials And Methods: The CRISPR/Cas9 knock out system was used to establish the YTHDF1 knock out (YTHDF1-KO) cell lines (HEK293 and HeLa) and METTL14 knock out (METTL14-KO) cell line (HEK293). 4SU-TT-seq was used to check the half-life changes of mRNAs. Actinomycin D and qPCR were used to test the half-life changes of individual mRNA. RNA was stained with SYTO RNA-select dye in wild type (WT) and YTHDF1-KO HeLa cell lines. Co-localization of YTHDF1 and AGO2 was identified by immunofluorescence. The interaction domain of YTHDF1 and AGO2 was identified by western blot. Phase separation of YTHDF1 was performed in vitro and in vivo. Fluorescence recovery after photobleaching (FRAP) was performed on droplets as an assessment of their liquidity.

Results: In this research, we found that deletion of YTHDF1 led to massive RNA patches deposited in cytoplasm. The results of 4SU-TT-seq showed that deletion of YTHDF1 would prolong the half-life of mRNAs. Immunofluorescence data showed that YTHDF1 and AGO2 could co-localize in P-body, and Co-IP results showed that YTHDF1 could interact with AGO2 through YT521-B homology (YTH) domain. We confirmed that YTHDF1 could undergo phase separation in vitro and in vivo, and compared with AGO2, YTHDF1 was more important in P-body formation. The FRAP results showed that liquid AGO2 droplets would convert to gel/solid when YTHDF1 was deleted. As AGO2 plays important roles in miRISCs, we also found that miRNA-mediate mRNA degradation is related to YTHDF1.

Conclusions: YTHDF1 recruits AGO2 through the YTH domain. YTHDF1 degrades targeting mRNAs by promoting P-body formation through LLPS. The deletion of YTHDF1 causes the P-body to change from liquid droplets to gel/solid droplets, and form AGO2/RNA patches, resulting in a degradation delay of mRNAs. These findings reveal a previously unrecognized crosstalk between YTHDF1 and AGO2, raising a new sight of mRNA post-transcriptional regulation by YTHDF1.
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http://dx.doi.org/10.1111/cpr.13157DOI Listing
November 2021

CSCD2: an integrated interactional database of cancer-specific circular RNAs.

Nucleic Acids Res 2022 Jan;50(D1):D1179-D1183

School of Basic Medical Sciences, Wuhan University, Wuhan430071, China.

The significant function of circRNAs in cancer was recognized in recent work, so a well-organized resource is required for characterizing the interactions between circRNAs and other functional molecules (such as microRNA and RNA-binding protein) in cancer. We previously developed cancer-specific circRNA database (CSCD), a comprehensive database for cancer-specific circRNAs, which is widely used in circRNA research. Here, we updated CSCD to CSCD2 (http://geneyun.net/CSCD2 or http://gb.whu.edu.cn/CSCD2), which includes significantly more cancer-specific circRNAs identified from a large number of human cancer and normal tissues/cell lines. CSCD2 contains >1000 samples (825 tissues and 288 cell lines) and identifies a large number of circRNAs: 1 013 461 cancer-specific circRNAs, 1 533 704 circRNAs from only normal samples and 354 422 circRNAs from both cancer and normal samples. In addition, CSCD2 predicts potential miRNA-circRNA and RBP-circRNA interactions using binding motifs from >200 RBPs and 2000 microRNAs. Furthermore, the potential full-length and open reading frame sequence of these circRNAs were also predicted. Collectively, CSCD2 provides a significantly enhanced resource for exploring the function and regulation of circRNAs in cancer.
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http://dx.doi.org/10.1093/nar/gkab830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728299PMC
January 2022

ADEIP: an integrated platform of age-dependent expression and immune profiles across human tissues.

Brief Bioinform 2021 11;22(6)

College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China.

Gene expression and immune status in human tissues are changed with aging. There is a need to develop a comprehensive platform to explore the dynamics of age-related gene expression and immune profiles across tissues in genome-wide studies. Here, we collected RNA-Seq datasets from GTEx project, containing 16 704 samples from 30 major tissues in six age groups ranging from 20 to 79 years old. Dynamic gene expression along with aging were depicted and gene set enrichment analysis was performed among those age groups. Genes from 34 known immune function categories and immune cell compositions were investigated and compared among different age groups. Finally, we integrated all the results and developed a platform named ADEIP (http://gb.whu.edu.cn/ADEIP or http://geneyun.net/ADEIP), integrating the age-dependent gene expression and immune profiles across tissues. To demonstrate the usage of ADEIP, we applied two datasets: severe acute respiratory syndrome coronavirus 2 and human mesenchymal stem cells-assoicated genes. We also included the expression and immune dynamics of these genes in the platform. Collectively, ADEIP is a powerful platform for studying age-related immune regulation in organogenesis and other infectious or genetic diseases.
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http://dx.doi.org/10.1093/bib/bbab274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344678PMC
November 2021

Silencing of circIgf1r plays a protective role in neuronal injury via regulating astrocyte polarization during epilepsy.

FASEB J 2021 02;35(2):e21330

Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Epilepsy is a common brain disorder, repeated seizures of epilepsy may lead to a series of brain pathological changes such as neuronal or glial damage. However, whether circular RNAs are involved in neuronal injury during epilepsy is not fully understood. Here, we screened circIgf1r in the status epilepticus model through circRNA sequencing, and found that it was upregulated after the status epilepticus model through QPCR analysis. Astrocytes polarizing toward neurotoxic A1 phenotype and neurons loss were observed after status epilepticus. Through injecting circIgf1r siRNA into the lateral ventricle, it was found that knocking down circIgf1r in vivo would induce the polarization of astrocytes to phenotype A2 and reduce neuronal loss. The results in vitro further confirmed that inhibiting the expression of circIgf1r in astrocytes could protect neurons by converting reactive astrocytes from A1 to the protective A2. In addition, knocking down circIgf1r in astrocytes could functionally promote astrocyte autophagy and relieve the destruction of 4-AP-induced autophagy flux. In terms of mechanism, circIgf1r promoted the polarization of astrocytes to phenotype A1 by inhibiting autophagy. Taken together, our results reveal circIgf1r may serve as a potential target for the prevention and treatment of neuron damage after epilepsy.
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http://dx.doi.org/10.1096/fj.202001737RRDOI Listing
February 2021

CircRNA inhibits DNA damage repair by interacting with host gene.

Mol Cancer 2020 08 24;19(1):128. Epub 2020 Aug 24.

School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China.

Background: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected.

Method: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities.

Results: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs.

Conclusion: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.
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http://dx.doi.org/10.1186/s12943-020-01246-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446195PMC
August 2020

Breath therapy for patients with chronic nonspecific low back pain: A protocol of systematic review and meta-analysis.

Medicine (Baltimore) 2020 Jul;99(31):e21542

Sichuan Provincial Orthopedics Hospital.

Background: Chronic nonspecific low back pain (CNLBP) has become a major global public health problem. Its high incidence rate and high disability rate are so damaging both to individuals and communities. At present, many countries' clinical guidelines recommend exercise therapy. Breath therapy is one of the exercise therapies, playing an important role in exercise therapy. Some studies have shown that breath therapy has a considerable therapeutic effect on low back pain, but there is no specific conclusion. The aim of our study is to answer the question: if breath therapy is effective and safe for CNLBP?

Methods: The following databases will be searched: English databases (including Web of Science, the Cochrane Library (Central), EMBASE, MEDLINE, Allied and Alternative Medicine) and Chinese databases (including Chinese National Knowledge Infrastructure, Wanfang data and Chinese Scientific Journals Database [VIP]). The literature search will be constructed around search terms for breath therapy, search terms for chronic nonspecific low back pain and search terms for randomized controlled trials. The primary outcomes were related to duration, intensity, attack frequency of pain, and the secondary outcomes were related to physical function, quality of life, and adverse events related to interventions. Endnote software 9.1 will be applied in selecting study, Review Manager software 5.3 will be applied in analyzing and synthesizing.

Results: The results will provide evidence to judge whether breath therapy is effective and safe for CNLBP.

Conclusion: Our research will provide reliable evidence of breath therapy for CNLBP.

Registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42020156340.
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http://dx.doi.org/10.1097/MD.0000000000021542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402803PMC
July 2020

GR/HDAC2/TGFβR1 pathway contributes to prenatal caffeine induced-osteoarthritis susceptibility in male adult offspring rats.

Food Chem Toxicol 2020 Jun 19;140:111279. Epub 2020 Mar 19.

Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address:

Prenatal caffeine exposure (PCE) induces developmental toxicity of multi-organ and susceptibility to multi-disease in offspring. However, the effects of PCE on osteoarthritis susceptibility in adult offspring and its intrauterine programming mechanism remain to be further investigated. Here, we found that PCE induced susceptibility to osteoarthritis in male adult offspring rats, which was related to the inhibited function of cartilage matrix synthesis from fetuses to adults. Meanwhile, PCE consistently downregulated the H3K9ac and expression levels of transforming growth factor β receptor 1 (TGFβR1), and then blocked TGFβ signaling pathway, which contributed to the suppressed cartilage matrix synthesis. Moreover, the high level of corticosterone caused by PCE reduced the H3K9ac level on TGFβR1 promoter region through acting on glucocorticoids receptor (GR) and recruiting histone deacetylase 2 (HDAC2) into the nucleus of fetal chondrocytes. Taken together, PCE induced osteoarthritis susceptibility in male adult offspring rats, which was attributed to the low-functional programming of TGFβR1 induced by corticosterone via GR/HDAC2 signaling.
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http://dx.doi.org/10.1016/j.fct.2020.111279DOI Listing
June 2020

The RNA N-methyladenosine modification landscape of human fetal tissues.

Nat Cell Biol 2019 05 29;21(5):651-661. Epub 2019 Apr 29.

Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N-methyladenosine (mA), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of mA in human tissues, we generated 21 whole-transcriptome mA methylomes across major fetal tissues using mA sequencing. These data reveal dynamic mA methylation, identify large numbers of tissue differential mA modifications and indicate that mA is positively correlated with gene expression homeostasis. We also report mA methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for mA. Tissue mA regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect mA modifications. Finally, we find that mA modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript mA. Our data indicate that mA is widely regulated by human genetic variation and promoters, suggesting a broad involvement of mA in human development and disease.
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http://dx.doi.org/10.1038/s41556-019-0315-4DOI Listing
May 2019

Genome-wide identification of cancer-specific alternative splicing in circRNA.

Mol Cancer 2019 03 8;18(1):35. Epub 2019 Mar 8.

School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China.

Circular RNA (circRNA) is a group of RNA families generated by RNA circularization, which was discovered ubiquitously across different cancers. However, the internal structure of circRNA is difficult to determine due to alternative splicing that occurs in its exons and introns. Furthermore, cancer-specific alternative splicing of circRNA is less likely to be identified. Here, we proposed a de novo algorithm, CircSplice, that could identify internal alternative splicing in circRNA and compare differential circRNA splicing events between different conditions ( http://gb.whu.edu.cn/CircSplice or https://github.com/GeneFeng/CircSplice ). By applying CircSplice in clear cell renal cell carcinoma and bladder cancer, we detected 4498 and 2977 circRNA alternative splicing (circ-AS) events in the two datasets respectively and confirmed the expression of circ-AS events by RT-PCR. We further inspected the distributions and patterns of circ-AS in cancer and adjacent normal tissues. To further understand the potential functions of cancer-specific circ-AS, we classified those events into tumor suppressors and oncogenes and performed pathway enrichment analysis. This study is the first comprehensive view of cancer-specific circRNA alternative splicing, which could contribute significantly to regulation and functional research of circRNAs in cancers.
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http://dx.doi.org/10.1186/s12943-019-0996-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408762PMC
March 2019

The prognostic value of matrix metalloproteinase-7 and matrix metalloproteinase-15 in acute myeloid leukemia.

J Cell Biochem 2019 06 27;120(6):10613-10624. Epub 2019 Feb 27.

Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, China.

Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are involved in a variety of physiological and pathological processes. We analyzed 11 data sets from Gene Expression Omnibus Database and found that MMP7 and MMP15 were highly expressed in multiple carcinomas. GSE13204 showed that MMP7 and MMP15 were overexpressed in acute myeloid leukemia (AML) patients. The Cancer Genome Atlas data set exhibited that high expression of MMP7 or MMP15 in bone marrow (BM) of AML patients predicted poor overall survival. The χ test results indicated that high expression level of MMP7 and MMP15 were correlated with high-risk stratification and high BM blast cell percentage in AML patients. To confirm these findings, we performed reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and found that MMP7 and MMP15 were highly expressed in three AML cell lines. Further study showed that MMP7 and MMP15 were highly expressed both in BM and peripheral blood in collected AML samples compared with healthy individuals. Additionally, long noncoding RNA (lncRNA) microarray of BM samples of AML patients revealed that multiple lncRNAs were correlated with MMP7 and MMP15, suggesting that lncRNAs might be involved in the pathogenesis of AML via modulating MMPs. In conclusion, our study uncovers the potential roles of MMP7 and MMP15 in the prognosis of AML.
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http://dx.doi.org/10.1002/jcb.28351DOI Listing
June 2019

CVm6A: A Visualization and Exploration Database for m⁶As in Cell Lines.

Cells 2019 02 17;8(2). Epub 2019 Feb 17.

School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei, China.

N6-methyladenosine (m⁶A) has been identified in various biological processes and plays important regulatory functions in diverse cells. However, there is still no visualization database for exploring global m⁶A patterns across cell lines. Here we collected all available MeRIP-Seq and m⁶A-CLIP-Seq datasets from public databases and identified 340,950 and 179,201 m⁶A peaks dependent on 23 human and eight mouse cell lines respectively. Those m⁶A peaks were further classified into mRNA and lncRNA groups. To better understand the potential function of m⁶A, we then mapped m⁶A peaks in different subcellular components and gene regions. Among those human m⁶A modification, 190,050 and 150,900 peaks were identified in cancer and non-cancer cells, respectively. Finally, all results were integrated and imported into a visualized cell-dependent m⁶A database CVm6A. We believe the specificity of CVm6A could significantly contribute to the research for the function and regulation of cell-dependent m⁶A modification in disease and development.
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http://dx.doi.org/10.3390/cells8020168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406471PMC
February 2019

Loss of miR-146b-5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL-17A pathway.

J Cell Biochem 2019 04 25;120(4):5936-5948. Epub 2018 Oct 25.

Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Metastatic disease remains the primary cause of death for individuals with T cell acute lymphoblastic leukemia (T-ALL). microRNAs (miRNAs) play important roles in the pathogenesis of T-ALL by inhibiting gene expression at posttranscriptional levels. The goal of the current project is to identify any significant miRNAs in T-ALL metastasis. We observed miR-146b-5p to be downregulated in T-ALL patients and cell lines, and bioinformatics analysis implicated miR-146b-5p in the hematopoietic system. miR-146b-5p inhibited the migration and invasion in T-ALL cells. Interleukin-17A (IL-17A) was predicted to be a target of miR-146b-5p; this was confirmed by luciferase assays. Interestingly, T-ALL patients and cell lines secreted IL-17A and expressed the IL-17A receptor (IL-17RA). IL-17A/IL-17RA interactions promoted strong T-ALL cell migration and invasion responses. Gene set enrichment analysis (GSEA) and quantitative polymerase chain reaction (qPCR) analysis indicated that matrix metallopeptidase-9 (MMP9), was a potential downstream effector of IL-17A activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was also implicated in this process. Moreover, IL-17A activation promoted T-ALL cell metastasis to the liver in IL17A mouse models. These results indicate that reduced miR-146b-5p expression in T-ALL may lead to the upregulation of IL-17A, which then promotes T-ALL cell migration and invasion by upregulating MMP9 via NF-κB signaling.
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http://dx.doi.org/10.1002/jcb.27882DOI Listing
April 2019

Author Correction: Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia.

Nat Commun 2018 02 9;9(1):670. Epub 2018 Feb 9.

Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.

The original version of this Article contained an error in the spelling of the author James C. Mulloy, which was incorrectly given as James Mulloy. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-02947-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807514PMC
February 2018

IGF1/MAPK/ERK signaling pathway-mediated programming alterations of adrenal cortex cell proliferation by prenatal caffeine exposure in male offspring rats.

Toxicol Appl Pharmacol 2018 02 16;341:64-76. Epub 2018 Jan 16.

Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China. Electronic address:

Our previous study proposed a glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming mechanism for prenatal caffeine exposure (PCE)-induced adrenal developmental dysfunction. Here, we focused on PCE-induced cell proliferation changes of the adrenal cortex in male offspring rats before and after birth and clarified the intrauterine programming mechanism. On gestational day (GD) 20, the PCE group had an elevated serum corticosterone level reduced fetal bodyweight, maximum adrenal sectional area, and elevated adrenal corticosterone and aldosterone contents. However, in postnatal week (PW) 6, the serum corticosterone level was decreased, and the bodyweight, with catch-up growth, adrenal cortex maximum cross-sectional area and aldosterone content were relatively increased, while the adrenal corticosterone content was lower. On GD20, the expression of adrenal IGF1, IGF1R and proliferating cell nuclear antigen (PCNA) were decreased, while the expression of these factors at PW6 were increased in the PCE group. Fetal adrenal gene chip analysis suggested that the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) signal pathway was suppressed in the PCE group. Moreover, in the rat primary adrenal cells, corticosterone (rather than caffeine) was shown to significantly inhibit cell proliferation, IGF1 and PCNA expression, and ERK phosphorylation, which could be reversed by exogenous IGF1. Meanwhile, the effects of exogenous IGF1 were reversed by the ERK pathway inhibitor (PD184161). In conclusion, PCE could induce programming alterations in adrenal cortical cell proliferation before and after birth in male offspring rats. The underlying mechanism is associated with the inhibition of fetal adrenal IGF1-related MAPK/ERK signaling pathway caused by high glucocorticoid levels.
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http://dx.doi.org/10.1016/j.taap.2018.01.008DOI Listing
February 2018

E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the and Oncogenes by Destabilizing the Histone Demethylase KDM5C.

Cancer Res 2018 03 16;78(6):1418-1430. Epub 2018 Jan 16.

Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes and Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like and This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2118DOI Listing
March 2018

Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia.

Nat Commun 2017 12 13;8(1):2099. Epub 2017 Dec 13.

Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.

Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
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http://dx.doi.org/10.1038/s41467-017-02290-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727390PMC
December 2017

CircView: a visualization and exploration tool for circular RNAs.

Brief Bioinform 2018 11;19(6):1310-1316

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School.

Circular RNAs (circRNAs) are novel rising stars of noncoding RNAs, which are highly abundant and evolutionarily conserved across species. Number of publications related to circRNAs increased sharply in recent years, representing emerging focuses in the field. Therefore, tools, pipelines and databases have been developed to identify and store circRNAs. However, there is no existing tool to visualize and explore circRNAs. Therefore, we introduce CircView, a user-friendly visualization tool for circRNAs detected from existing tools. CircView enables users to visualize circRNAs and to quantify number of samples with detected circRNAs. CircView allows users to explore circRNAs detected by unique or multiple tools. Furthermore, CircView allows users to view the regulatory elements, such as microRNA response elements and RNA-binding protein binding sites. CircView is a unique tool to visualize and explore circRNAs, which helps users to better understand potential functions of circRNAs and design the functional experiments.
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http://dx.doi.org/10.1093/bib/bbx070DOI Listing
November 2018

CSCD: a database for cancer-specific circular RNAs.

Nucleic Acids Res 2018 01;46(D1):D925-D929

School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei, China.

Circular RNA (circRNA) is a large group of RNA family extensively existed in cells and tissues. High-throughput sequencing provides a way to view circRNAs across different samples, especially in various diseases. However, there is still no comprehensive database for exploring the cancer-specific circRNAs. We collected 228 total RNA or polyA(-) RNA-seq samples from both cancer and normal cell lines, and identified 272 152 cancer-specific circRNAs. A total of 950 962 circRNAs were identified in normal samples only, and 170 909 circRNAs were identified in both tumor and normal samples, which could be further used as non-tumor background. We constructed a cancer-specific circRNA database (CSCD, http://gb.whu.edu.cn/CSCD). To understand the functional effects of circRNAs, we predicted the microRNA response element sites and RNA binding protein sites for each circRNA. We further predicted potential open reading frames to highlight translatable circRNAs. To understand the association between the linear splicing and the back-splicing, we also predicted the splicing events in linear transcripts of each circRNA. As the first comprehensive cancer-specific circRNA database, we believe CSCD could significantly contribute to the research for the function and regulation of cancer-associated circRNAs.
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http://dx.doi.org/10.1093/nar/gkx863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753219PMC
January 2018

Genome-wide characterization of lncRNAs in acute myeloid leukemia.

Brief Bioinform 2018 07;19(4):627-635

School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Long noncoding RNAs (lncRNAs) are a large family of noncoding RNAs that play a critical role in various normal bioprocesses as well as tumorigenesis. However, the expression patterns and biological functions of lncRNAs in acute leukemia have not been well studied. Here, we performed transcriptome-wide lncRNA expression profiling of acute myeloid leukemia (AML) patient samples, along with non-leukemia control hematopoietic samples. We found that lncRNAs were differentially expressed in AML samples relative to control samples. Notably, we identified that lncRNAs upregulated in AML (relative to the control samples) are associated with a lower degree of DNA methylation and a higher ratio of being bound by transcription factors such as SP1, STAT4, ATF-2 and ELK-1 compared with those downregulated in AML. Moreover, an enrichment of H3K4me3 and a depletion of H3K27me3 were observed in upregulated lncRNAs in AML. Expression patterns of three types of lncRNAs (antisense, enhancer and intergenic lncRNAs) have previously been characterized. Of the identified lncRNAs, we found that high expression level lncRNA LOC285758 is associated with the poor prognosis in AML patients. Furthermore, we found that LOC285758 regulates proliferation of AML cell lines by enhancing the expression of HDAC2, a key factor in carcinogenesis. Collectively, our study depicts a landscape of important lncRNAs in AML and provides novel potential therapeutic targets and prognostic markers for AML treatment.
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http://dx.doi.org/10.1093/bib/bbx007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355113PMC
July 2018

Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome.

J Am Coll Cardiol 2016 11;68(19):2086-2096

Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiovascular Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California. Electronic address:

Background: Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder.

Objectives: The objective of this study was to examine single cell mechanism of Brugada syndrome using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Methods: This study recruited 2 patients with type 1 BrS carrying 2 different sodium voltage-gated channel alpha subunit 5 variants as well as 2 healthy control subjects. We generated iPSCs from their skin fibroblasts by using integration-free Sendai virus. We used directed differentiation to create purified populations of iPSC-CMs.

Results: BrS iPSC-CMs showed reductions in inward sodium current density and reduced maximal upstroke velocity of action potential compared with healthy control iPSC-CMs. Furthermore, BrS iPSC-CMs demonstrated increased burden of triggered activity, abnormal calcium (Ca) transients, and beating interval variation. Correction of the causative variant by genome editing was performed, and resultant iPSC-CMs showed resolution of triggered activity and abnormal Ca transients. Gene expression profiling of iPSC-CMs showed clustering of BrS compared with control subjects. Furthermore, BrS iPSC-CM gene expression correlated with gene expression from BrS human cardiac tissue gene expression.

Conclusions: Patient-specific iPSC-CMs were able to recapitulate single-cell phenotype features of BrS, including blunted inward sodium current, increased triggered activity, and abnormal Ca handling. This novel human cellular model creates future opportunities to further elucidate the cellular disease mechanism and identify novel therapeutic targets.
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http://dx.doi.org/10.1016/j.jacc.2016.07.779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373649PMC
November 2016

Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes.

Brief Bioinform 2017 Nov;18(6):984-992

Circular RNA (circRNA) is a group of RNA family generated by RNA circularization, which was discovered ubiquitously across different species and tissues. However, there is no global view of tissue specificity for circRNAs to date. Here we performed the comprehensive analysis to characterize the features of human and mouse tissue-specific (TS) circRNAs. We identified in total 302 853 TS circRNAs in the human and mouse genome, and showed that the brain has the highest abundance of TS circRNAs. We further confirmed the existence of circRNAs by reverse transcription polymerase chain reaction (RT-PCR). We also characterized the genomic location and conservation of these TS circRNAs and showed that the majority of TS circRNAs are generated from exonic regions. To further understand the potential functions of TS circRNAs, we identified microRNAs and RNA binding protein, which might bind to TS circRNAs. This process suggested their involvement in development and organ differentiation. Finally, we constructed an integrated database TSCD (Tissue-Specific CircRNA Database: http://gb.whu.edu.cn/TSCD) to deposit the features of TS circRNAs. This study is the first comprehensive view of TS circRNAs in human and mouse, which shed light on circRNA functions in organ development and disorders.
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http://dx.doi.org/10.1093/bib/bbw081DOI Listing
November 2017

Glycine confers neuroprotection through microRNA-301a/PTEN signaling.

Mol Brain 2016 05 26;9(1):59. Epub 2016 May 26.

Department of Physiology, School of Basic Medical Sciences, Medical Research Institute, Wuhan University School of Medicine, 185 Donghu Street, Wuhan, 430071, China.

Background: Glycine is known to protect against neuronal death. However, the underlying mechanism remains to be elucidated. The microRNA-301a is involved in both biological and pathological processes. But it is not known whether microRNA-301a has a neuroprotective property. In this study, we aimed to determine whether glycine-induced neuroprotection requires microRNA-301a-dependent signaling.

Results: We provided the first evidence that glycine increased the expression of microRNA-301a in cultured rat cortical neurons and protected against cortical neuronal death through up-regulation of microRNA-301a after oxygen-glucose deprivation. MicroRNA-301a directly bound the predicted 3'UTR target sites of PTEN and reduced PTEN expression in cortical neurons. We revealed that PTEN down-regulation by microRNA-301a mediated glycine-induced neuroprotective effect following oxygen-glucose deprivation.

Conclusions: Our results suggest that 1) microRNA-301a is neuroprotective in oxygen-glucose deprivation-induced neuronal injury; 2) glycine is an upstream regulator of microRNA-301a; 3) glycine confers neuroprotection through microRNA-301a/PTEN signal pathway.
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http://dx.doi.org/10.1186/s13041-016-0241-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880874PMC
May 2016

Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis.

Oncotarget 2016 Apr;7(17):23552-68

Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.

Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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http://dx.doi.org/10.18632/oncotarget.8083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029647PMC
April 2016

Systematic Characterization of Long Noncoding RNAs Reveals the Contrasting Coordination of Cis- and Trans-Molecular Regulation in Human Fetal and Adult Hearts.

Circ Cardiovasc Genet 2016 Apr 19;9(2):110-8. Epub 2016 Feb 19.

From the Stanford Cardiovascular Institute (C.H., K.D.W., H.W., J.C., J.C.W.), Division of Cardiology, Department of Medicine (C.H., H.W., J.C., J.C.W.), Department of Pathology (K.D.W.), and Program in Epithelial Biology (K.Q., H.Y.C.), Stanford University, CA; and School of Basic Medical Science (C.H., H.H., S.X.) and International School of Software (J.F.), Wuhan University, Wuhan, China.

Background: The molecular regulation of heart development is regulated by cis- and trans-factors acting on the genome and epigenome. As a class of important regulatory RNAs, the role of long noncoding RNAs (lncRNAs) in human heart development is still poorly understood. Furthermore, factors that interact with lncRNAs in this process are not well characterized.

Methods And Results: Using RNA sequencing, we systematically define the contrasting lncRNA expression patterns between fetal and adult hearts. We report that lncRNAs upregulated in adult versus fetal heart have different sequence features and distributions. For example, the adult heart expresses more sense lncRNAs compared with fetal heart. We also report the coexpression of lncRNAs and neighboring coding genes that have important functions in heart development. Importantly, the regulation of lncRNA expression during fetal to adult heart development seems to be due, in part, to the coordination of specific developmental epigenetic modifications, such as H3K4me1 and H3k4me3. The expression of promoter-associated lncRNAs in adult and fetal hearts also seems to be related to these epigenetic states. Finally, transcription factor-binding analysis suggests that lncRNAs are directly regulating cardiac gene expression during development.

Conclusions: We provide a systematic analysis of lncRNA control of heart development that gives clues to the roles that specific lncRNAs play in fetal and adult hearts.
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http://dx.doi.org/10.1161/CIRCGENETICS.115.001264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862831PMC
April 2016

Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism.

Eur Heart J 2015 Apr 2;36(13):806-16. Epub 2014 Nov 2.

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

Aims: High-fat diet-induced obesity (DIO) is a major contributor to type II diabetes and micro- and macro-vascular complications leading to peripheral vascular disease (PVD). Metabolic abnormalities of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from obese individuals could potentially limit their therapeutic efficacy for PVD. The aim of this study was to compare the function of iPSC-ECs from normal and DIO mice using comprehensive in vitro and in vivo assays.

Methods And Results: Six-week-old C57Bl/6 mice were fed with a normal or high-fat diet. At 24 weeks, iPSCs were generated from tail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayer approach. In vitro functional analysis revealed that iPSC-ECs from DIO mice had significantly decreased capacity to form capillary-like networks, diminished migration, and lower proliferation. Microarray and ELISA confirmed elevated apoptotic, inflammatory, and oxidative stress pathways in DIO iPSC-ECs. Following hindlimb ischaemia, mice receiving intramuscular injections of DIO iPSC-ECs had significantly decreased reperfusion compared with mice injected with control healthy iPSC-ECs. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving DIO iPSC-ECs. When pravastatin was co-administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, N(ω)-nitro-l-arginine methyl ester.

Conclusion: This is the first study to provide evidence that iPSC-ECs from DIO mice exhibit signs of endothelial dysfunction and have suboptimal efficacy following transplantation in a hindlimb ischaemia model. These findings may have important implications for future treatment of PVD using iPSC-ECs in the obese population.
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http://dx.doi.org/10.1093/eurheartj/ehu411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381134PMC
April 2015

TET1 plays an essential oncogenic role in MLL-rearranged leukemia.

Proc Natl Acad Sci U S A 2013 Jul 1;110(29):11994-9. Epub 2013 Jul 1.

Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
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http://dx.doi.org/10.1073/pnas.1310656110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718141PMC
July 2013

miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia.

Proc Natl Acad Sci U S A 2013 Jul 24;110(28):11511-6. Epub 2013 Jun 24.

Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.

MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genomewide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease.
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http://dx.doi.org/10.1073/pnas.1310144110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710804PMC
July 2013

The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells.

J Biol Chem 2013 Jun 7;288(25):18439-47. Epub 2013 May 7.

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping with its role in aging, we demonstrated that human dermal fibroblasts (HDFs) from older human subjects were more resistant to reprogramming by classic Yamanaka factors than those from younger human subjects, but the addition of SIRT6 during reprogramming improved such efficiency in older HDFs substantially. Despite the importance of SIRT6, little is known about the molecular mechanism of its regulation. We show, for the first, time posttranscriptional regulation of SIRT6 by miR-766 and inverse correlation in the expression of this microRNA in HDFs from different age groups. Our results suggest that SIRT6 regulates miR-766 transcription via a feedback regulatory loop, which has implications for the modulation of SIRT6 expression in reprogramming of aging cells.
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http://dx.doi.org/10.1074/jbc.M112.405928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689986PMC
June 2013

Identification of a 24-gene prognostic signature that improves the European LeukemiaNet risk classification of acute myeloid leukemia: an international collaborative study.

J Clin Oncol 2013 Mar 4;31(9):1172-81. Epub 2013 Feb 4.

University of Chicago, Chicago, IL 60637, USA.

Purpose: To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification.

Patients And Methods: Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses.

Results: A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS.

Conclusion: Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.
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http://dx.doi.org/10.1200/JCO.2012.44.3184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595425PMC
March 2013
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