Modern technological advances, like the unraveling of the human genome, high-throughput cellular processes, etc., have ushered in an era with renewed hope for better health for the world. ...Sophisticated tools have been developed for diagnosing, curing, and preventing diseases. There has been extraordinary development in understanding the human genome and its role in health and disease. A decade ago, researchers tentatively explored the first reference human genome at the cost of more than $1 billion. However, now thousands of genomes from different ethnic backgrounds have been sequenced. This explosion of sequencing has been enabled by unprecedented advances in sequencing technologies that can now sequence a person?s entire genome within a day at a nominal cost of $1,000 (or less). Technology advances enable an ever?increasing capacity to diagnose existing diseases and develop novel treatment strategies accurately. Such technologies also offer clinicians the opportunities to identify potential biomarkers. However, the enormous information generated from these technologies has posed challenging propositions to develop novel practical biotechnology and medicine applications. Although our knowledge of the human genome is far from complete, accumulating examples demonstrate that even our limited genomic understanding can have robust clinical implications. From stem cell therapy to improved blood tests to a variety of pharmaceuticals, the face of healthcare has been changed by biotechnology. Biotechnology companies use microbes to create new therapeutic agents, such as monoclonal antibodies, antibiotics, vaccines, and hormones. Five years ago, scientists at J. Craig Venter Institute collaborated with researchers at MIT to develop an artificial cell with only 473 genes. This genetically engineered simplest bacterium is considered one of the pillars of synthetic biology. Introducing Re:GEN Open Given the exciting state of affairs in biomedical research, I am particularly excited to be named as founding editor of the new multidisciplinary open-access journal, Re:GEN Open. I have always been interested in studying the role of genomics in translational research. I started in genomic projects at the University of Illinois at Chicago and worked on microbial virulence factors and their role in cancer. I learned some of the critical intricacies of the genome from my mentor, A.M. Chakrabarty. Dr. Chakrabarty is credited with creating and patenting the first genetically engineered oil-eating bacterium?Pseudomonas aeruginosa?which revolutionized genetic engineering and biotechnology. I continued my work on the relationship of microorganisms with cancer at the University of Pittsburgh focusing on viral-mediated oncogenesis in various malignancies. During that time, massively parallel sequencing was taking off, and I focused on human genome sequencing and its relation to the development and progression of cancer. My work took me deep into synthetic and systems biology at the University of Southern California. My current research focuses on developing genomic-based precision medicine strategies for various diseases, emphasizing biomarker discovery. I have been on many adventures in the genomics industry and have helped people by providing potential precision medicine solutions. Re:GEN Open is unique because it combines different biomedical research areas in a single forum. We hope to attract stakeholders in academia, industry, as well as medical professionals around the world. We would love to hear from researchers and professionals who are innovators in drug development, stem cell or DNA/RNA-based therapies, and their patient-specific studies. The journal will cover all aspects of basic and translational biomedical research under eight broad sections: Basic Biomedical Research Translational Biomedical Research Drug Development Cancer Research Regenerative Medicine Cell and Gene Therapy Infectious Disease Synthetic and Systems Biology Synthetic biotechnology is reshaping the way humans live, but only a few journals are dedicated to this field. Therefore, we have a separate section dedicated to this evolving branch of biotechnology. In launching Re:GEN Open, I envisage the journal playing a central role in supporting the rapid development of the genetic engineering and biotechnology field in which we operate. To achieve this, we will: make effective and speedy editorial decisions; expand our presence in emerging and developing areas of genetic engineering and biotechnology; work with the editorial advisory board to champion new and emerging fields and scale the journal ranks in these areas; strengthen and facilitate our relationship with many other fine journals published by Mary Ann Liebert Inc., publishers, by allowing the transfer of quality papers to Re:GEN Open. With our publisher?s continued support, we will aim for the highest standards in the journal?s management and operations; give priority to papers that are scientifically rigorous and make a significant advance in the biomedical sciences and publish them after one round of reviews; and consider manuscripts that have been reviewed and rejected by leading journals such as Nature, Science, PNAS, JCI, etc. Based on reviewers? and authors? rebuttal comments, the AEs will advise if the manuscript needs further review or can be published directly. It is an honor and privilege for me to work alongside incoming editorial board members representing a broad and diverse group of scientists with varied intellectual interests and career paths. Our editorial board members have volunteered their expertise and time. They are committed to making Re:GEN Open the best journal publishing studies of the impact on biotechnology on biomedical sciences. I shall be seeking their advice to improve the journal?s standing, exploring developing areas in genetic engineering, biotechnology, and the life sciences. In addition to our balance in the editorial team, we are committed to providing fair and rigorous but timely peer review. Our processes will ensure fairness and trust from submission to final decision. Open Access Re:GEN Open is a fully open access journal. To promote unhindered dissemination of laboratory research, we will support the principles of open access to all colleagues across the world, regardless of their financial or educational background. We also believe in open data sharing to ensure reproducibility in published results. Open access publications can reduce some of the barriers in sharing data, protocols, and source codes. Articles will be swiftly posted on the journal?s website upon acceptance and be freely available. In conclusion, I hope you enjoy reading some of our first published articles and look forward to many more exciting articles in the months and years to come. I hope you will want to shape and develop the journal in the future with your discoveries. Most importantly, please share your thoughts about Re:GEN Open with your colleagues and contribute your research to our journal so we may learn together and make the world healthier. Finally, I would like to remind the journal?s readers that this journal belongs to you. If you have any suggestions or constructive criticism that may help our team improve any aspects of our journal, please email us at editorial@regenopen.com. You can also send us presubmission inquiries to this email to check whether your next manuscript is a good fit. Cheers! Vasu Punj
Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAF
-melanoma, autophagy is induced by ...BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAF
via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the "BRAF-TFEB-autophagy-lysosome" axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.
Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through specific downstream transcription factors. In this study, we used tooth root ...development as a model with which to investigate how the BMP signaling pathway regulates transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1
cells. Using a Gli1-driven Cre-mediated recombination system, our results provide the first
evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified the transcription factors Pax9, Klf4, Satb2 and Lhx8 as being downstream of BMP signaling and expressed in a spatially restricted pattern that is potentially involved in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, which is associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating MSC fate during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.
Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is ...induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of genes involved in mitochondrial metabolic pathways required to maintain tumor-initiating stem-like cells (TICs). NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, as well as ROS generation, and activates fatty acid oxidation (FAO) to support TIC self-renewal and drug resistance. Restoration of OXPHOS activity and inhibition of FAO renders TICs susceptible to a standard care chemotherapy drug for HCC, sorafenib. This study provides insights into the mechanisms of NANOG-mediated generation of TICs, tumorigenesis, and chemoresistance through reprogramming of mitochondrial metabolism.
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•Stem cell marker NANOG is activated by the TLR4-E2F1 pathway•NANOG ChIP-seq identifies target genes involved in OXPHOS and FAO•Nanog represses OXPHOS and mitochondrial ROS in TICs•Restoration of OXPHOS and inhibition of FAO restores TIC susceptibility to drugs
Chen et al. show that the pluripotency transcription factor NANOG contributes to liver cancer progression by reprogramming mitochondrial metabolism to promote self-renewal ability, tumor-initiation property, and chemoresistance of tumor-initiating stem-like cells (TICs). Restoration of OXPHOS activity and inhibition of fatty acid oxidation restores TIC susceptibility to chemotherapy drugs.
Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here, we demonstrate that PAI-1 promotes the recruitment and M2 ...polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and nuclear factor κB (NF-κB) and induction of an autocrine interleukin (IL)-6/STAT3 activation pathway. We then show in several experiments in mice that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6, and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6, and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer.
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•PAI-1 promotes monocyte migration via its N-terminal LRP binding domain•PAI-1 promotes M2 macrophage polarization via its C-terminal uPA interacting domain•The action on macrophage polarization is via an IL-6/STAT3 autocrine loop
The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) has a paradoxical pro-angiogenic and protective effect on cancer cells. Kubala et al. provide evidence for a third pro-tumorigenic function by demonstrating that PAI-1 promotes recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages.
Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) ...is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.
Although limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, the specific genomic sites targeted for H3NT proteolysis and the ...functional significance of H3NT cleavage remain largely unknown. Here we report the first method to identify and examine H3NT-cleaved regions in mammals, called chromatin immunoprecipitation (ChIP) of acetylated chromatin (ChIPac). By applying ChIPac combined with deep sequencing (ChIPac-seq) to an established cell model of osteoclast differentiation, we discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most H3NT-cleaved genes displayed significant expression changes during osteoclastogenesis. We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). In contrast to other known H3NT proteases, MMP-9 primarily cleaved H3K18-Q19 in vitro and in cells. Furthermore, our results support CBP/p300-mediated acetylation of H3K18 as a central regulator of MMP-9 H3NT protease activity both in vitro and at H3NT cleavage sites during osteoclastogenesis. Importantly, we found that abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. Our collective results support the necessity of MMP-9-dependent H3NT proteolysis in regulating gene pathways required for proficient osteoclastogenesis.
SET and MYND domain containing protein 3 (SMYD3) is a histone methyltransferase, which has been implicated in cell growth and cancer pathogenesis. Increasing evidence suggests that SMYD3 can ...influence distinct oncogenic processes by acting as a gene-specific transcriptional regulator. However, the mechanistic aspects of SMYD3 transactivation and whether SMYD3 acts in concert with other transcription modulators remain unclear. Here, we show that SMYD3 interacts with the human positive coactivator 4 (PC4) and that such interaction potentiates a group of genes whose expression is linked to cell proliferation and invasion. SMYD3 cooperates functionally with PC4, because PC4 depletion results in the loss of SMYD3-mediated H3K4me3 and target gene expression. Individual depletion of SMYD3 and PC4 diminishes the recruitment of both SMYD3 and PC4, indicating that SMYD3 and PC4 localize at target genes in a mutually dependent manner. Artificial tethering of a SMYD3 mutant incapable of binding to its cognate elements and interacting with PC4 to target genes is sufficient for achieving an active transcriptional state in SMYD3-deficient cells. These observations suggest that PC4 contributes to SMYD3-mediated transactivation primarily by stabilizing SMYD3 occupancy at target genes. Together, these studies define expanded roles for SMYD3 and PC4 in gene regulation and provide an unprecedented documentation of their cooperative functions in stimulating oncogenic transcription.
Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly ...understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Leprdb/db mice that produce leptin, we provide evidence of a central role for the leptin-TISC–signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.
OBJECTIVE: To evaluate genome-wide DNA methylation patterns in sperm from men with abnormal sperm chromatin packaging and patients displaying abnormal embryogenesis after IVF in the absence of known ...female factors. DESIGN: Case–control study. SETTING: University andrology and research laboratory. PATIENT(S): Men with abnormally high and low protamine 1/protamine 2 ratio (n = 15); patients who have undergone IVF/intracytoplasmic sperm injection resulting in abnormal embryogenesis (n = 13); and normozoospermic, fertile controls (n = 15). INTERVENTION(S): Genome-wide sperm DNA methylation was measured using the Illumina Infinium HumanMethylation27 BeadChip assay. Follow-up targeted methylation analysis was performed using bisulfite pyrosequencing. MAIN OUTCOME MEASURE(S): Methylation levels at more than 27,000 CpGs genome-wide were compared between groups. RESULT(S): Of the 43 men analyzed, 40 displayed highly concordant methylation patterns; however, two men with abnormal protamine 1/protamine 2 and one abnormal embryogenesis patient displayed significantly altered methylation patterns across a large number of CpGs. Imprinted regions were more prone to deregulation than the genome at large. CONCLUSION(S): We have identified three individuals displaying broad disruption of sperm DNA methylation profiles. Although the sample set analyzed is relatively small, these results indicate that broad disruptions in sperm DNA methylation may be an important signature in some infertile men. Functional studies will be necessary to characterize the developmental consequences of such epigenetic disruption.
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