Sang Woo Kim

Brown University, Providence, Rhode Island, United States

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Publications (8)104.72 Total impact

  • Sang Woo Kim, Kyoung Joo Cho
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    ABSTRACT: Fragile X syndrome (FXS), the most common cause of inherited human mental retardation, results from the loss of function of fragile X mental retardation protein (FMRP). To date, most researchers have thought that FXS neural pathologies are primarily caused by extreme dendritic branching and spine formation. With this rationale, several researchers attempted to prune dendritic branches and reduce the number of spines in FXS animal models. We propose that increased dendritic arborization and spinogenesis in FXS are developed rather as secondary compensatory responses to counteract the compromised postsynaptic activity during uncontrollable metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD). When postsynaptic and electrical activities become dampened in FXS, dendritic trees can increase their sensitivity to brain-derived neurotrophic factor (BDNF) by using the molecular sensor called eukaryotic elongation factor 2 (eEF2) and taking advantage of the tight coupling of mGluR and BDNF-TrkB signaling pathways. Then, this activity-dependent elevation of the BDNF signaling can strategically alter dendritic morphologies to foster branching and develop spine structures in order to improve the postsynaptic response in FXS. Our model suggests a new therapeutic rationale for FXS: correcting the postsynaptic and electrical activity first, and then repairing structural abnormalities of dendrites. Then, it may be possible to successfully fix the dendritic morphologies without affecting the survival of neurons. Our theory may also be generalized to explain aberrant dendritic structures observed in other neurobehavioral diseases, such as tuberous sclerosis, Rett syndrome, schizophrenia, and channelopathies, which accompany high postsynaptic and electrical activity.
    Medical Hypotheses. 01/2014;
  • Sang Woo Kim, Kyoung Joo Cho, Byung In Lee
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    ABSTRACT: Tight linkages between metabolic states and cerebral cortical excitability have been observed and may be enabled by orexinergic neurons in the lateral hypothalamus (LH). However, despite reports of the close relationship between "dysfunction" in metabolism and "dysfunction" in cerebral cortical excitability, a mechanism has yet to be proposed to explain this coupling. We propose that the "compensatory actions" of orexinergic neurons in the LH may enable the coupling of metabolic and cortical dysfunction. When metabolites are inefficiently utilized during metabolic dysfunction with insulin/leptin resistance, orexinergic neurons can be activated to initiate negative feedback by triggering sympathetic innervation to elevate compromised catabolism. Activated orexinergic neurons as an intentional metabolic compensation, however, may unintentionally cause cortical dysfunction in the end by making the cortex, thalamus, and hippocampus hyperexcitable. Similarly, during cortical dysfunction, activated orexinergic neurons can trigger negative feedback on unstably high cortical rhythms by increasing food intake, which can potentially relieve cortical excitability via hypothalamic satiety modulation mechanisms. However, hyperphagia, an intentional cortical compensation, metabolically challenges bodies and eventually may result in metabolic dysfunction. Our model proposes a new therapeutic rationale for metabolic and cortical disorders. We suggest that by maintaining the negative feedback loop mediated by orexinergic neurons intact and pharmacologically blocking unintentional branches that may give rise to new types of dysfunction, the vicious cycle of metabolic and cortical dysfunction can be avoided.
    Medical Hypotheses 03/2013; · 1.18 Impact Factor
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    ABSTRACT: We present a comprehensive map of over 1 million polyadenylation sites and quantify their usage in major cancers and tumor cell lines using direct RNA sequencing. We built the Expression and Polyadenylation Database to enable the visualization of the polyadenylation maps in various cancers and to facilitate the discovery of novel genes and gene isoforms that are potentially important to tumorigenesis. Analyses of polyadenylation sites indicate that a large fraction (∼30%) of mRNAs contain alternative polyadenylation sites in their 3' untranslated regions, independent of the cell type. The shortest 3' untranslated region isoforms are preferentially upregulated in cancer tissues, genome-wide. Candidate targets of alternative polyadenylation-mediated upregulation of short isoforms include POLR2K, and signaling cascades of cell-cell and cell-extracellular matrix contact, particularly involving regulators of Rho GTPases. Polyadenylation maps also helped to improve 3' untranslated region annotations and identify candidate regulatory marks such as sequence motifs, H3K36Me3 and Pabpc1 that are isoform dependent and occur in a position-specific manner. In summary, these results highlight the need to go beyond monitoring only the cumulative transcript levels for a gene, to separately analysing the expression of its RNA isoforms.
    Nucleic Acids Research 06/2012; 40(17):8460-71. · 8.81 Impact Factor
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    ABSTRACT: The emerging discoveries on the link between polyadenylation and disease states underline the need to fully characterize genome-wide polyadenylation states. Here, we report comprehensive maps of global polyadenylation events in human and yeast generated using refinements to the Direct RNA Sequencing technology. This direct approach provides a quantitative view of genome-wide polyadenylation states in a strand-specific manner and requires only attomole RNA quantities. The polyadenylation profiles revealed an abundance of unannotated polyadenylation sites, alternative polyadenylation patterns, and regulatory element-associated poly(A)(+) RNAs. We observed differences in sequence composition surrounding canonical and noncanonical human polyadenylation sites, suggesting novel noncoding RNA-specific polyadenylation mechanisms in humans. Furthermore, we observed the correlation level between sense and antisense transcripts to depend on gene expression levels, supporting the view that overlapping transcription from opposite strands may play a regulatory role. Our data provide a comprehensive view of the polyadenylation state and overlapping transcription.
    Cell 12/2010; 143(6):1018-29. · 31.96 Impact Factor
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    ABSTRACT: Small (<200 nucleotide) RNA (sRNA) profiling of human cells using various technologies demonstrates unexpected complexity of sRNAs with hundreds of thousands of sRNA species present. Genetic and in vitro studies show that these RNAs are not merely degradation products of longer transcripts but could indeed have a function. Furthermore, profiling of RNAs, including the sRNAs, can reveal not only novel transcripts, but also make clear predictions about the existence and properties of novel biochemical pathways operating in a cell. For example, sRNA profiling in human cells indicated the existence of an unknown capping mechanism operating on cleaved RNA, a biochemical component of which was later identified. Here we show that human cells contain a novel type of sRNA that has non-genomically encoded 5' poly(U) tails. The presence of these RNAs at the termini of genes, specifically at the very 3' ends of known mRNAs, strongly argues for the presence of a yet uncharacterized endogenous biochemical pathway in cells that can copy RNA. We show that this pathway can operate on multiple genes, with specific enrichment towards transcript-encoding components of the translational machinery. Finally, we show that genes are also flanked by sense, 3' polyadenylated sRNAs that are likely to be capped.
    Nature 07/2010; 466(7306):642-6. · 38.60 Impact Factor
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    ABSTRACT: The continuing discoveries of potentially active small RNAs at an unprecedented rate using high-throughput sequencing have raised the need for methods that can reliably detect and quantitate the expression levels of small RNAs. Currently, northern blot is the most widely used method for validating small RNAs that are identified by methods such as high-throughput sequencing. We describe a new northern blot-based protocol (LED) for small RNA (approximately 15-40 bases) detection using digoxigenin (DIG)-labeled oligonucleotide probes containing locked nucleic acids (LNA) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide for cross-linking the RNA to the membrane. LED generates clearly visible signals for RNA amounts as low as 0.05 fmol. This method requires as little as a few seconds of membrane exposure to outperform the signal intensity using overnight exposure of isotope-based methods, corresponding to approximately 1000-fold improvement in exposure-time. In contrast to commonly used radioisotope-based methods, which require freshly prepared and hazardous probes, LED probes can be stored for at least 6 months, facilitate faster and more cost-effective experiments, and are more environmentally friendly. A detailed protocol of LED is provided in the Supplementary Data.
    Nucleic Acids Research 04/2010; 38(7):e98. · 8.81 Impact Factor
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    Genome Biology 01/2010; · 10.30 Impact Factor
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    ABSTRACT: Recently identified small (20 to 40 bases) RNAs, such as microRNAs (miRNAs) and endogenous small interfering RNAs (siRNAs) participate in important cellular pathways. In this report, we systematically characterized several novel features of human and viral RNA products smaller than miRNAs. We found that Kaposi sarcoma-associated herpesvirus K12-1 miRNA (23 bases) associates with a distinct, unusually small (17-base) RNA (usRNA) that can effectively downregulate a K12-1 miRNA target, human RAD21, suggesting that stable degradation-like products may also contribute to gene regulation. High-throughput sequencing reveals a diverse set of human miRNA-derived usRNAs and other non-miRNA-derived usRNAs. Human miRNA-derived usRNAs preferentially match to 5' ends of miRNAs and are also more likely to associate with the siRNA effector protein Ago2 than with Ago1. Many non-miRNA-derived usRNAs associate with Ago proteins and also frequently contain C-rich 3'-specific motifs that are overrepresented in comparison to Piwi-interacting RNAs and transcription start site-associated RNAs. We postulate that approximately 30% of usRNAs could have evolved to participate in biological processes, including gene silencing.
    Journal of Virology 10/2009; 83(24):12751-8. · 5.08 Impact Factor

Publication Stats

231 Citations
104.72 Total Impact Points

Institutions

  • 2013–2014
    • Brown University
      • Department of Neuroscience
      Providence, Rhode Island, United States
  • 2009–2010
    • University of Pittsburgh
      • Department of Computational & Systems Biology
      Pittsburgh, PA, United States