Recursos de colección

DSpace at MIT (104.280 recursos)

This site is a university repository providing access to the publication output of the institution. Registered users can set up email alerts to notify them of newly added relevant content. A certain level of encryption and security is embedded in the site which may cause some users accessibility problems.

MIT Open Access Articles

Mostrando recursos 1 - 20 de 29.900

  1. Ten years of genetics and genomics: what have we achieved and where are we heading?

    Heard, Edith; Tishkoff, Sarah; Todd, John A.; Vidal, Marc; Wagner, Günter P.; Wang, Jun; Weigel, Detlef; Young, Richard A
    To celebrate the first 10 years of Nature Reviews Genetics, we asked eight leading researchers for their views on the key developments in genetics and genomics in the past decade and the prospects for the future. Their responses highlight the incredible changes that the field has seen, from the explosion of genomic data and the many possibilities it has opened up to the ability to reprogramme adult cells to pluripotency. The way ahead looks similarly exciting as we address questions such as how cells function as systems and how complex interactions among genetics, epigenetics and the environment combine to shape...

  2. Functional Association of Gdown1 with RNA Polymerase II Poised on Human Genes

    Cheng, Bo; Li, Tiandao; Rahl, Peter B.; Adamson, Todd E.; Loudas, Nicholas B.; Guo, Jiannan; Varzavand, Katayoun; Cooper, Jeffrey J.; Hu, Xiaopeng; Gnatt, Averell; Price, David H.; Young, Richard A
    Most human genes are loaded with promoter-proximally paused RNA polymerase II (Pol II) molecules that are poised for release into productive elongation by P-TEFb. We present evidence that Gdown1, the product of the POLR2M gene that renders Pol II responsive to Mediator, is involved in Pol II elongation control. During in vitro transcription, Gdown1 specifically blocked elongation stimulation by TFIIF, inhibited the termination activity of TTF2, and influenced pausing factors NELF and DSIF, but did not affect the function of TFIIS or the mRNA capping enzyme. Without P-TEFb, Gdown1 led to the production of stably paused polymerases in the presence...

  3. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer

    Heyn, Holger; Vidal, Enrique; Ferreira, Humberto J.; Vizoso, Miguel; Sayols, Sergi; Gomez, Antonio; Moran, Sebastian; Boque-Sastre, Raquel; Guil, Sonia; Martinez-Cardus, Anna; Royo, Romina; Sanchez-Mut, Jose V.; Martinez, Ramon; Gut, Marta; Torrents, David; Orozco, Modesto; Gut, Ivo; Esteller, Manel; Lin, Charles; Young, Richard A
    Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results: Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is...

  4. Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control

    Hnisz, Denes; Day, Daniel S.; Young, Richard A
    Understanding how transcriptional enhancers control over 20,000 protein-coding genes to maintain cell-type-specific gene expression programs in all human cells is a fundamental challenge in regulatory biology. Recent studies suggest that gene regulatory elements and their target genes generally occur within insulated neighborhoods, which are chromosomal loop structures formed by the interaction of two DNA sites bound by the CTCF protein and occupied by the cohesin complex. Here, we review evidence that insulated neighborhoods provide for specific enhancer-gene interactions, are essential for both normal gene activation and repression, form a chromosome scaffold that is largely preserved throughout development, and are perturbed...

  5. Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

    Tan, Justin L.; Fogley, Rachel D.; Flynn, Ryan A.; Ablain, Julien; Yang, Song; Do, Brian T.; Laga, Alvaro C.; Fujinaga, Koh; Santoriello, Cristina; Greer, Celeste B.; Kim, Yoon Jung; Clohessy, John G.; Bothmer, Anne; Pandell, Nicole; Avagyan, Serine; Brogie, John E.; van Rooijen, Ellen; Hagedorn, Elliott J.; Shyh-Chang, Ng; White, Richard M.; Price, David H.; Pandolfi, Pier Paolo; Peterlin, B. Matija; Zhou, Yi; Kim, Tae Hoon; Asara, John M.; Chang, Howard Y.; Zon, Leonard I.; Saint-André, Violaine; Fan, Zi Peng; Young, Richard A
    Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration...

  6. Starving leukemia to induce differentiation

    Cheng, Chia-Wei; Yilmaz, Omer
    A new study shows that fasting induces the differentiation and elimination of some types of leukemia in mice, which implicates fasting or its mimetics as a novel strategy for the treatment of this disease.

  7. Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system

    Jijon, H B; Diaz, O E; Das, S; De Calisto, J; Pittet, M J; Mora, J R; Belkaid, Y; Xavier, R J; Villablanca, E J; Yaffe, Michael B; Suarez Lopez, Lucia
    Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4 + goblet cell precursors in the distal bowel,...

  8. RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors

    Dreaden, Erik; Kong, Yi Wen; Quadir, Mohiuddin Abdul; Correa Echavarria, Santiago; Suarez Lopez, Lucia; Barberio, Antonio Eric; Hwang, Mun Kyung; Shi, Aria C.; Oberlton, Benjamin J.; Gallagher, Paige N.; Shopsowitz, Kevin; Elias, Kevin; Yaffe, Michael B; Hammond, Paula T
    DNA damaging chemotherapy is a cornerstone of current front‐line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo‐resistant disease; therefore, adjuvant treatments that synergize with DNA‐damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex‐mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high‐grade serous OC to...

  9. Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles

    Vu Han, Tu-Lan; Balkanska-Sinclair, Elena; Floyd, Scott R; Lam, Fred Chiu-Lai; Morton, Stephen Winford; Wyckoff, Jeffrey; Vu-Han, Tu-Lan; Hwang, Mun Kyung; Maffa, Amanda; Yaffe, Michael B; Hammond, Paula T
    Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5-to 2-fold decrease in tumor burden and corresponding...

  10. Two CYP82D Enzymes Function as Flavone Hydroxylases in the Biosynthesis of Root-Specific 4′-Deoxyflavones in Scutellaria baicalensis

    Zhao, Qing; Cui, Meng-Ying; Yang, Dongfeng; Liu, Jie; Li, Jie; Hill, Lionel; Yang, Lei; Hu, Yonghong; Chen, Xiao-Ya; Martin, Cathie; Levsh, Olesya; Weng, Jing-Ke
    Baicalein, wogonin, and their glycosides are major bioactive compounds found in the medicinal plant Scutellaria baicalensis Georgi. These flavones can induce apoptosis in a variety of cancer cell lines but have no effect on normal cells. Furthermore, they have many additional benefits for human health, such as anti-oxidant, antiviral, and liver-protective properties. Here, we report the isolation and characterization of two CYP450 enzymes, SbCYP82D1.1 and SbCYP82D2, which function as the flavone 6-hydroxylase (F6H) and flavone 8-hydroxylase (F8H), respectively, in S. baicalensis. SbCYP82D1.1 has broad substrate specificity for flavones such as chrysin and apigenin and is responsible for biosynthesis of baicalein...

  11. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

    Prabhala, Harsha; Mestdagh, Pieter; Muth, Daniel; Teruya-Feldstein, Julie; Westermann, Frank; Speleman, Frank; Vandesompele, Jo; Ma, Li-Jun; Young, Jennifer J; Pan, Elizabeth; Reinhardt, Ferenc; Onder, Tamer T; Valastyan, Scott John; Weinberg, Robert A
    MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells...

  12. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model

    Reinhardt, Ferenc; Pan, Elizabeth; Soutschek, Jürgen; Bhat, Balkrishen; Marcusson, Eric G; Teruya-Feldstein, Julie; Bell, George W; Ma, Li; Weinberg, Robert A
    MicroRNAs (miRNAs) are increasingly implicated in the regulation of metastasis. Despite their potential as targets for anti-metastatic therapy, miRNAs have only been silenced in normal tissues of rodents and nonhuman primates. Therefore, the development of effective approaches for sequence-specific inhibition of miRNAs in tumors remains a scientific and clinical challenge. Here we show that systemic treatment of tumor-bearing mice with miR-10b antagomirsa class of chemically modified anti-miRNA oligonucleotidesuppresses breast cancer metastasis. Both in vitro and in vivo, silencing of miR-10b with antagomirs significantly decreases miR-10b levels and increases the levels of a functionally important miR-10b target, Hoxd10. Administration of miR-10b...

  13. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells?

    Scheel, Christina; Weinberg, Robert A
    Cancer stem cells (CSCs) are similar to normal stem cells in their ability to self-renew and to generate large populations of more differentiated descendants. In contrast to the hierarchical organization that is presumed to be the prevalent mode of normal tissue homeostasis, phenotypic plasticity allows cancer cells to dynamically enter into and exit from stem-cell states. The epithelial-mesenchymal transition (EMT) has been closely associated with the acquisition of both invasive and stem-cell properties in cancer cells. Thereby, EMT programs emerge as important regulators of phenotypic plasticity in cancer cells including their entrance into stem-cell states. Much is still to be...

  14. Cancer-Stimulated Mesenchymal Stem Cells Create a Carcinoma Stem Cell Niche via Prostaglandin E

    Li, Hua-Jung; Herschman, Harvey R.; Reinhardt, Ferenc; Weinberg, Robert A
    Mesenchymal cells of the tumor-associated stroma are critical determinants of carcinoma cell behavior. We focus here on interactions of carcinoma cells with mesenchymal stem cells (MSC), which are recruited to the tumor stroma and, once present, are able to influence the phenotype of the carcinoma cells. We find that carcinoma cell–derived interleukin-1 (IL-1) induces prostaglandin E₂(PGE₂) secretion by MSCs. The resulting PGE₂ operates in an autocrine manner, cooperating with ongoing paracrine IL-1 signaling, to induce expression of a group of cytokines by the MSCs. The PGE₂ and cytokines then proceed to act in a paracrine fashion on the carcinoma cells...

  15. The Outgrowth of Micrometastases Is Enabled by the Formation of Filopodium-like Protrusions

    Shibue, Tsukasa; Brooks, Mary W.; Inan, M. Fatih; Reinhardt, Ferenc; Weinberg, Robert A
    Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix components to survive, proliferate, and form macroscopic metastases. The biochemical and cell biologic mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated integrin β1-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase. These plaques originate in and appear only after the formation of filopodium-like protrusions (FLP) that harbor integrin β1 along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to...

  16. Tackling the cancer stem cells — what challenges do they pose?

    Pattabiraman, Diwakar R.; Weinberg, Robert A
    Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas...

  17. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells

    Ye, Xin; Tam, Wai Leong; Shibue, Tsukasa; Kaygusuz, Yasemin; Ng Eaton, Elinor; Reinhardt, Ferenc; Weinberg, Robert A
    Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers. Analogies between TICs and normal tissue stem cells have led to the proposal that activation of the normal stem-cell program within a tissue serves as the major mechanism for generating TICs. Supporting this notion, we and others previously established that the Slug epithelial-to-mesenchymal transition-inducing transcription factor (EMT-TF), a member of the Snail family, serves as a master regulator of the gland-reconstituting activity of normal mammary stem cells, and that forced expression of Slug in collaboration with Sox9 in breast cancer cells can efficiently induce...

  18. Epithelial–Mesenchymal Plasticity: A Central Regulator of Cancer Progression

    Ye, Xin; Weinberg, Robert A
    The epithelial-mesenchymal transition (EMT) program has emerged as a central driver of tumor malignancy. Moreover, the recently uncovered link between passage through an EMT and acquisition of stem-like properties indicates that activation of the EMT programs serves as a major mechanism for generating cancer stem cells (CSCs); that is, a subpopulation of cancer cells that are responsible for initiating and propagating the disease. In this review, we summarize the evidence supporting the widespread involvement of the EMT program in tumor pathogenesis and attempt to rationalize the connection between the EMT program and acquisition of stem cell traits. We propose that...

  19. How Does Multistep Tumorigenesis Really Proceed?

    Chaffer, Christine L.; Weinberg, Robert A
    Identifying the cancer cells-of-origin is of great interest, as it holds the potential to elucidate biologic mechanisms inherent in the normal cell state that have been co-opted to drive the oncogenic cell state. An emerging concept, proposed here, states that cancer stem cells, key players in cancer initiation and metastasis, arise when transit-amplifying cells with mutant genomes dedifferentiate and enter the stem cell state. This model contrasts with the notion that cancer stem cells are the direct products of neoplastically transformed normal tissue stem cells.

  20. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability

    Pattabiraman, D. R.; Bierie, B.; Kober, K. I.; Thiru, P.; Krall, J. A.; Zill, C.; Reinhardt, F.; Tam, W. L.
    The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming...

Aviso de cookies: Usamos cookies propias y de terceros para mejorar nuestros servicios, para análisis estadístico y para mostrarle publicidad. Si continua navegando consideramos que acepta su uso en los términos establecidos en la Política de cookies.