Download OMB No. 0925-0001/0002 (Rev. 08/12), Biographical Sketch Format

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
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NAME: Huang, Yingqun
eRA COMMONS USER NAME (credential, e.g., agency login):
POSITION TITLE: Associate Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE
(if
applicable)
Completion
Date
MM/YYYY
Shanghai Medical University, China
B.S., M.D.
05/88
Medicine
Shanghai Medical University, China
M.S.
05/91
Pathophysiology
University of Connecticut Health Center
Ph.D.
05/97
Biomedical Sciences
University of Connecticut Health Center
Postdoctoral
07/99
Molecular Biology
Yale University School of Medicine
Postdoctoral
07/03
Molecular Biology
INSTITUTION AND LOCATION
FIELD OF STUDY
A. Personal Statement
Since my graduate student days I have been interested in a variety of aspects of RNA processing. An early
interest was in the rules and mechanisms that govern the nuclear-to-cytoplasmic transport of mRNAs in
mammalian cells. As a PhD student I focused on identification and characterization of cis-acting regulatory
RNA elements. During my postdoctoral training I discovered a subset of SR proteins (serine/arginine repeatscontaining proteins) as a novel class of mRNA export factors. I further showed that these factors interact with
both cis-acting RNA elements and the essential mRNA export protein NXF1 to promote mRNA export and that
this process is regulated by protein phosphorylation. The research provided me with extensive experience and
expertise in the study of RNA, RNA-binding proteins, and posttranscriptional regulation of gene expression.
During the early stage as an independent investigator, I received research funds from the State of
Connecticut to study the RNA-binding protein Lin28 in human embryonic stem (ES) cells. Through research
into the role of Lin28 in the proliferation and differentiation of ES cells, I expanded my gene regulation
repertoire and gained experience in genome-wide studies (RNA-seq) and computational data analysis. The
field had once believed that blocking the biogenesis of let-7 microRNA was the only function of Lin28. My
research however helped to shift the field to accept that Lin28 is also a master posttranscriptional regulator of a
subset of mRNAs involved in regulating cell growth and metabolism. This research resulted in a total of 13
publications within a period of five years.
For the past five years my interest has extended to the H19 lncRNA as a result of my serendipitous
discovery that H19 functions as a molecular “sponge” for the microRNA let-7. Recently, I discovered the
secretory signaling molecule BMP8B as yet another novel target of H19 regulation via an unanticipated
epigenetic mechanism. Together, these studies led to three major papers (Molecular Cell, Nucleic Acids
Research, and Nature Communications) and form the basis for the current proposal.
Despite being an “elderly” New Investigator, I have demonstrated a consistent record of successful and
fruitful research projects involved in posttranscriptional and epigenetic regulation of gene expression as well as
recent metabolic studies using transgenic mouse models. My experience and expertise have positioned me
perfectly for successful completion of the proposed studies.
Thinking “out-of-box” and perseverance are additional strengths that I believe have characterized my
scientific career.
B. Positions and Honors
Positions and Employment
1997-1999 Postdoctoral Fellow, Department of Microbiology, University of Connecticut Health Center, CT
1999-2003 Postdoctoral Fellow, Department of Molecular Biophysics & Biochemistry, Yale University
School of Medicine, CT
2003-2010 Assistant Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale
University School of Medicine, CT
2010Associate Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale
University School of Medicine, CT
Other Experience and Professional Memberships
2013Member, American Diabetes Association
2010Associate Editor, Frontiers in Non-coding RNA
2014Editorial board member, Endocrinology
Honors
1988 Rong-Ling’s Award for Graduation with Distinction in Medicine, Fudan University School of Medicine,
Shanghai, China
1997 Edward G. Henderson Memorial Prize for outstanding Ph.D. thesis in Biomedical Sciences,
University of Connecticut Health Center, Farmington, CT
1999 US Patent No. 5,990,298, University of Connecticut: "Cis-acting Cellular Nucleic Acid Molecules" Gordon G. Carmichael and Yingqun Huang, inventors
2006 Technology licensing, Yale University: “Development of a polyclonal antibody specific for the mouse
NXF2” - Yingqun Huang, inventor
2007 Patent pending (PCT 47162-5016-00-WO), Yale University: “Cellular delivery of siRNA” - Yingqun
Huang, inventor
2013 Harold Behrman Teaching Award, Dept of Ob/Gyn & Reprod Sci., Yale University
C. Contribution to Science
1. During my postdoctoral training I mapped an mRNA export element in the intronless histone H2a mRNA to a
small region and used this sequence as an affinity reagent to identify cellular proteins that mediate its effects
on export. This work led to the discovery of a subset of SR proteins as new class of mRNA export factors.
These factors, which were originally thought to act solely as mRNA splicing factors, interact not only with many
mRNA export elements but also with the essential mRNA export protein NXF1/TAP to promote mRNA export. I
further established that this process is regulated by phosphorylation.
a. Huang Y, Steitz JA. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA.
Mol Cell. 2001 Apr;7(4):899-905. PubMed PMID: 11336712.
b. Huang Y, Gattoni R, Stévenin J, Steitz JA. SR splicing factors serve as adapter proteins for TAPdependent mRNA export. Mol Cell. 2003 Mar;11(3):837-43. PubMed PMID: 12667464.
c. Huang Y, Yario TA, Steitz JA. A molecular link between SR protein dephosphorylation and mRNA
export. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9666-70. Epub 2004 Jun 21. PubMed PMID:
15210956; PubMed Central PMCID: PMC470732.
d. Huang Y, Steitz JA. SRprises along a messenger's journey. Mol Cell. 2005 Mar 4;17(5):613-5. Review.
PubMed PMID: 15749011.
2. As an independent investigator, I studied the function of the RNA binding protein Lin28, which is highly
expressed in human embryonic stem (ES) cells and is among four factors shown to reprogram somatic cells to
induced pluripotent stem cells. The field had once believed that blocking the biogenesis of let-7 microRNA was
the only function of Lin28. My research however has shifted the field to accept that Lin28 is also a master
posttranscriptional regulator of a subset of mRNAs involved in regulating cell growth and metabolism.
a. Qiu C, Ma Y, Wang J, Peng S, Huang Y. Lin28-mediated post-transcriptional regulation of Oct4
expression in human embryonic stem cells. Nucleic Acids Res. 2010 Mar;38(4):1240-8. doi:
10.1093/nar/gkp1071. Epub 2009 Dec 4. PubMed PMID: 19966271; PubMed Central PMCID:
PMC2831306
b. Peng S, Chen LL, Lei XX, Yang L, Lin H, Carmichael GG, Huang Y. Genome-wide studies reveal that
Lin28 enhances the translation of genes important for growth and survival of human embryonic stem
cells. Stem Cells. 2011 Mar;29(3):496-504. doi: 10.1002/stem.591. PubMed PMID: 21425412.
c. Jin J, Jing W, Lei XX, Feng C, Peng S, Boris-Lawrie K, Huang Y. Evidence that Lin28 stimulates
translation by recruiting RNA helicase A to polysomes. Nucleic Acids Res. 2011 May;39(9):3724-34.
doi: 10.1093/nar/gkq1350. Epub 2011 Jan 18. PubMed PMID: 21247876; PubMed Central PMCID:
PMC3089476.
d. Huang Y. A mirror of two faces: Lin28 as a master regulator of both miRNA and mRNA. Wiley
Interdiscip Rev RNA. 2012 Jul-Aug;3(4):483-94. doi: 10.1002/wrna.1112. Epub 2012 Mar 29. Review.
PubMed PMID: 22467269.
3. Ovarian cancer is characterized by a high frequency of disease recurrence and the development of drug
resistance, which present major challenges to the treatment of this disease. Evidence suggests that this may
be due to the presence of “cancer stem cell” (CSC)-like cells within the tumors that have the capacity to
reproduce and to differentiate into non-CSC tumor cells that repopulate the tumor mass. My lab was the first to
show that a sub-population of ovarian cancer cells expresses Lin28 and Oct4, two major stem cell markers.
We also identified a significant synergistic effect of the double knockdown of Lin28 and Oct4 on cancer cell
growth and survival. Our findings have important implications for the existence of CSCs in ovarian cancer, and
the diagnostic methods may be useful for the identification and elimination of this important tumor cell
subpopulation.
a. Peng S, Maihle NJ, Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem
cell-like cells in ovarian cancer. Oncogene. 2010 Apr 8;29(14):2153-9. doi: 10.1038/onc.2009.500.
Epub 2010 Jan 25. PubMed PMID: 20101213.
b. Ma W, Ma J, Xu J, Qiao C, Branscum A, Cardenas A, Baron AT, Schwartz P, Maihle NJ, Huang Y.
Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment. Cell Cycle.
2013 Jan 1;12(1):88-97. doi: 10.4161/cc.23028. Epub 2012 Dec 19. PubMed PMID: 23255092;
PubMed Central PMCID: PMC3570521.
c. c. Feng C, Neumeister V, Ma W, Xu J, Lu L, Bordeaux J, Maihle NJ, Rimm DL, Huang Y. Lin28
regulates HER2 and promotes malignancy through multiple mechanisms. Cell Cycle. 2012 Jul
1;11(13):2486-94. doi: 10.4161/cc.20893. Epub 2012 Jul 1. PubMed PMID: 22713243.
4. The developmentally regulated, imprinted H19 lncRNA has long been implicated in human genetic disorders
and cancer. However, the physiological function and mode of action of this conserved lncRNA have remained
elusive. Using gene knockdown and overexpression, combined with genome-wide transcriptome analysis, we
show that H19 harbors both canonical and noncanonical binding sites for microRNA let-7 and it inhibits let-7
function by acting as a molecular “sponge”. We highlight the physiological significance of our findings by
showing that depletion of H19 causes precocious muscle differentiation, a phenotype recapitulated by let-7
overexpression in vitro. As let-7s comprise a major microRNA family known to play important roles in
development, cancer, and metabolism, our discovery has far-reaching impact on all of these areas.
a. Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, Lu L, Liu C, Yi JS, Zhang H, Min W, Bennett AM,
Gregory RI, Ding Y, Huang Y. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013
Oct 10;52(1):101-12. doi: 10.1016/j.molcel.2013.08.027. Epub 2013 Sep 19. PubMed PMID: 24055342;
PubMed Central PMCID: PMC3843377.
b. Yan L, Zhou J, Gao Y, Ghazal S, Lu L, Bellone S, Yang Y, Liu N, Zhao X, Santin AD, Taylor H, Huang
Y. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformininduced DNA methylation. Oncogene. 2015 Jun 4;34(23):3076-84. doi: 10.1038/onc.2014.236. Epub
2014 Aug 4. PubMed PMID: 25088204.
5. I have recently discovered a new function of H19: it binds to and inhibits the enzymatic activity of Sadenosylhomocysteine hydrolase (SAHH), thereby altering DNA methylation in a genome-wide fashion. Our
results uncover an unanticipated regulatory circuit involving broad epigenetic alterations by a single abundantly
expressed lncRNA that may underlie gene methylation dynamics of development and diseases. Indeed, our
recent Oncogene paper revealed that this H19-mediated epigenetic regulatory mechanism underlies the anticancer activity of metformin in human cancer.
a. Zhou J,Yang L, Zhong T, Mueller M, Men Y, Zhang N, Xie J, Giang K, Chung H, Sun X, Lu L, Carmichael
GG, Taylor HS, Huang Y. H19 lncRNA alters DNA methylation genome wide by regulating Sadenosylhomocysteine hydrolase. Nat Commun. 2015 Dec 21;6:10221. doi: 10.1038/ncomms10221.
PMID: 26687445.
b. Zhong T, Men Y, Lu L, Geng T, Zhou J, Mitsuhashi A, Shozu M, Maihle NJ, Carmichael GG, Taylor HS,
Huang Y. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene. 2016
Oct 24. doi: 10.1038/onc.2016.391. PMID: 27775072
Complete List of Published Work in MyBibliography:
http://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/
D. Research Support
Ongoing Research Support
7-14-BS-084
Huang (PI)
07/01/2015-06/30/2018
American Diabetes Association Basic Research Award
Mechanism of H19 long noncoding RNA-mediated regulation of glucose metabolism
The goal of this award is to determine the biological significance of interactions of H19 with identified partner
proteins using in vitro derived muscle cells.
Completed Research Support
09SCAYALE14 (Huang)
Huang (PI)
07/01/2009-06/30/2013
Connecticut Stem Cell Grant Program
Molecular function of Lin28 in human embryonic stem cells
The goal of this study is to elucidate the molecular function of Lin28 in hESC proliferation and differentiation.
1063338 McKern Scholar
Huang (PI)
02/01/2011-01/31/2013
Albert McKern Scholar Award
Role of activated decidual cells in natural killer cell recruitment and preeclampsia
The goal of this study is to determine whether activated first trimester decidual cells play a role in transforming
peripheral NK cell to decidual NK cells.