Entity

Time filter

Source Type


Falahati H.,Princeton University | Pelham-Webb B.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Blythe S.,Princeton University | Blythe S.,Howard Hughes Medical Institute | And 2 more authors.
Current Biology | Year: 2016

Membrane-less organelles are intracellular compartments specialized to carry out specific cellular functions. There is growing evidence supporting the possibility that such organelles form as a new phase, separating from cytoplasm or nucleoplasm. However, a main challenge to such phase separation models is that the initial assembly, or nucleation, of the new phase is typically a highly stochastic process and does not allow for the spatiotemporal precision observed in biological systems. Here, we investigate the initial assembly of the nucleolus, a membrane-less organelle involved in different cellular functions including ribosomal biogenesis. We demonstrate that the nucleolus formation is precisely timed in D. melanogaster embryos and follows the transcription of rRNA. We provide evidence that transcription of rRNA is necessary for overcoming the highly stochastic nucleation step in the formation of the nucleolus, through a seeding mechanism. In the absence of rDNA, the nucleolar proteins studied are able to form high-concentration assemblies. However, unlike the nucleolus, these assemblies are highly variable in number, location, and time at which they form. In addition, quantitative study of the changes in the nucleoplasmic concentration and distribution of these nucleolar proteins in the wild-type embryos is consistent with the role of rRNA in seeding the nucleolus formation. © 2016 Elsevier Ltd. Source


Roy D.M.,Sloan Kettering Cancer Center | Roy D.M.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Walsh L.A.,Sloan Kettering Cancer Center | Chan T.A.,Sloan Kettering Cancer Center
Protein and Cell | Year: 2014

Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies. © 2014 The Author(s). Source


Chinenov Y.,The David Rosensweig Genomics Center | Chinenov Y.,The New School | Coppo M.,The David Rosensweig Genomics Center | Gupte R.,The New School | And 3 more authors.
BMC Genomics | Year: 2014

Background: Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood. Results: We investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers. Conclusions: Pro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation. © 2014 Chinenov et al.; licensee BioMed Central Ltd. Source


Huang Y.-H.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program
Journal of Religion and Health | Year: 2013

The proliferation of patents on human genes has raised important ethical questions centered on the conflict of patient rights and intellectual property rights. With the Supreme Court's June 2013 decision that altered the patent eligibility of genetic material, it is important to reexamine the ethical implications of gene patents as a concept. Such patents suggest an ownership of genetic material that may hinder access to healthcare and inhibit medical progress. The application of the current patent system to genetic material thus violates patients' rights without fulfilling the system's goal of promoting innovation, suggesting a need for a revised incentives infrastructure. © 2013 Springer Science+Business Media New York. Source


Kleppe M.,Sloan Kettering Cancer Center | Kwak M.,Yale University | Koppikar P.,Sloan Kettering Cancer Center | Riester M.,Dana-Farber Cancer Institute | And 25 more authors.
Cancer Discovery | Year: 2015

The identifi cation of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofi brosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve effi cacy has not been delineated. Patients with MPN present with increased levels of circulating proinfl ammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profi ling demonstrated that hematopoietic cells from myelofi brosis models and patient samples aberrantly secrete infl ammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar effi cacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. © 2015 American Association for Cancer Research. Source

Discover hidden collaborations