David Kuo,

"Nothing in Biology Makes Sense Except in the Light of Evolution" - Dobzhansky (1973)

PhD Student

E-Mail
dkuo@get-your-addresses-elsewhere.inf.ethz.ch
Phone
+1 646 331 8884
Address
MSKCC – Computational Biology Center
1275 York Avenue, Box # 357
New York, NY 10065
Room
MSKCC: Z-677, HSS: 8th Floor
twitter
@dkuo

I studied Biology at Stanford University and worked as a Developer at McMaster-Carr Supply

Company before beginning my PhD studies in Systems Biology at Weill Cornell Medicine in New York City.

I began biomedical research in the laboratory of alternative splicing expert Jane Wu in the summers from 2001-2005. I earned my BS in Biological Sciences at Stanford University in 2008. While at Stanford, I performed research in the laboratory of cancer biologist Calvin Kuo (no relation), where we studied the effects of VEGF blockade on liver vasculature. After college, I worked as an Information Systems Developer for McMaster-Carr Supply Company before matriculating at the Weill Cornell Graduate School of Medical Sciences in the Physiology, Biophysics & Systems Biology Department. I joined the Rätsch Lab in 2012 with primary interests in genomics and biological data analysis. I collaborate actively with the laboratories of Lionel Ivashkiv at Hospital for Special Surgery and the Hans-Guido Wendel at MSKCC.

Abstract During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

Authors Loupasakis K, Kuo D, Sokhi UK, Sohn C, Syracuse B, Giannopoulou EG, Park SH, Kang H, Rätsch G, Ivashkiv LB, Kalliolias GD

Submitted PLoS One

Link DOI

Abstract MOTIVATION:Deep sequencing based ribosome footprint profiling can provide novel insights into the regulatory mechanisms of protein translation. However, the observed ribosome profile is fundamentally confounded by transcriptional activity. In order to decipher principles of translation regulation, tools that can reliably detect changes in translation efficiency in case-control studies are needed. RESULTS: We present a statistical framework and an analysis tool, RiboDiff, to detect genes with changes in translation efficiency across experimental treatments. RiboDiff uses generalized linear models to estimate the over-dispersion of RNA-Seq and ribosome profiling measurements separately, and performs a statistical test for differential translation efficiency using both mRNA abundance and ribosome occupancy. AVAILABILITY AND IMPLEMENTATION: RiboDiff webpage http://bioweb.me/ribodiff Source code including scripts for preprocessing the FASTQ data are available at http://github.com/ratschlab/ribodiff CONTACTS: zhongy@cbio.mskcc.org or raetsch@inf.ethz.chSupplementary information: Supplementary data are available at Bioinformatics online.

Authors Zhong Y, Karaletsos T, Drewe P, Sreedharan VT, Kuo D, Singh K, Wendel HG, Rätsch G.

Submitted Bioinformatics

Link DOI

Abstract Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

Authors K Wei, SM Piecewicz, LM McGinnis, CM Taniguchi, SJ Wiegand, K Anderson, CW M Chan, KX Mulligan, David Kuo, J Yuan, M Vallon, LC Morton, E Lefai, MC Simon, JJ Maher, G Mithieux, F Rajas, JP Annes, OP McGuinness, G Thurston, AJ Giaccia, CJ Kuo

Submitted Nat Med

Link DOI