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NAME: Christine Cheng
eRA COMMONS USER NAME (credential, e.g., agency login): CHENGCS
POSITION TITLE: Assistant Professor of Biology
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
National Taiwan University
B.S.
1996
Plant Biology
Stanford University
M.S.
2001
Computer Science
University of California, San Diego
Ph.D.
2011
Broad Institute of MIT and Harvard
Postdoctoral
2016
Bioinformatics and
Systems Biology
Epigenetics,
immunology, single cell
INSTITUTION AND LOCATION
FIELD OF STUDY
A. Personal Statement
This project proposes a novel approach to utilize massively parallel single-cell functional genomic assay that
can profile simultaneously thousands of single cells in each experiment to study human genetics. We propose to
develop an integrated single-cell resolution experimental and computational platform to identify genetic
variants that are responsible for changes in gene expression and epigenetic states. Furthermore, we will validate
the function of these genetic variants with massively parallel reporter assays in relevant cell types.
My long-term research interest is in the development of a comprehensive understanding of the gene regulatory
network and how aberrant regulatory circuits contribute to human disease, particularly in substance use
disorder. With a background in both experimental biology and computational sciences, my research approach
has been multi-interdisciplinary. During my Ph.D. and postdoctoral training, my main research interest was in
understanding the transcriptional and epigenetic regulation of the innate and adaptive immune responses. As a
graduate student with Dr. Alexander Hoffmann (UC San Diego), I combined top down (functional genomic
methods) and bottom up (kinetic modeling) systems biology approaches to dissect the innate immune response
transcriptional regulatory network (Cheng et al., Science Signaling 2011; Cheng et al., Cell Systems, accepted
for publication). As a postdoctoral fellow in the lab of Dr. Aviv Regev (Broad Institute of MIT and Harvard), I
developed a chromatin immunoprecipitation sequencing library preparation (ChIP-seq) protocol for the
semiconductor based sequencing platform, Ion Torrent (Cheng et al., Nature Communications 2013). In my
second project, I developed experimental and computational pipelines to map expression and epigenetic
quantitative trait loci (eQTL and epigenetic-QTL) by profiling RNA-seq and chromatin accessibility (by
ATAC-seq) in the primary T cells from 105 individuals (Cheng et al., Submitted to Science, in review). In my
third project, I utilized recently developed massively parallel single-cell RNA-seq that allows profiling of
thousands of individual single cells simultaneously and single-cell ATAC-seq to characterize the gene
expression and epigenetic variability between individual bone marrow derived dendritic cells in response to
pathogens (Cheng et al., in preparation).
The focus of my laboratory at Boston University lies at the interface of experimental biology and
bioinformatics, where we utilize and develop novel massively parallel single-cell epigenomic and
transcriptomic technologies and apply these to characterize heterogeneous populations in clinical samples. For
the long run, we will build computational models that allow us to predict disease progression and enable the
development of personalized medicine in the future.
B. Position and Honors
Research positions
2000
Graduate Research Assistant, Stanford University, Genome Technology Center
2000-2001
Graduate Research Assistant, Stanford University, Department of Statistics
2003-2006
Graduate Research Assistant, University of California, San Diego.
Mentor: Prof. Michael Rosenfeld
2006-2011
Graduate Research Assistant, University of California, San Diego.
Thesis Advisor: Prof. Alexander Hoffmann
2011-2016
Postdoctoral Fellow, Broad Institute of MIT and Harvard, Cambridge, MA
Mentor: Prof. Aviv Regev
2016-present Assistant Professor, Department of Biology, Bioinformatics Program, Boston University, Boston
Visiting Scholar, Broad Institute of MIT and Harvard, Cambridge, MA
Professional positions
2001-2002
Business Analyst, McKinsey and Company, Business Technology Office, Palo Alto, CA
2002-2003
Software Engineer, Oracle Corporation, Oracle Warehouse Builder
Fellowships and Awards
2005-2008
DOD Army Breast Cancer Predoctoral Traineeship
2012-2015
NIH Individual Postdoctoral Fellowship
C. Contribution to Science
1. Deciphering transcriptional regulatory network of the innate immune response by combining top down
and bottom up approaches
As a graduate student in the lab of Alexander Hoffmann at the University of California, San Diego I initiated a
novel research direction by combing functional genomics (top down) and mechanistic modeling (bottom up)
approaches to dissect transcriptional regulatory network in innate immune response. In my first study, I found a
novel role of NFkB p50 homodimer in cross regulating a newly defined guanine-rich IRE motif in addition to
the canonical NFkB binding motif. Mathematical modeling predicts that the newly identified role of NFkB p50
homodimer thereby restricting interferon signaling and antiviral immune responses only to appropriate
pathogens and the prediction was validated with viral infection experiments in macrophages. In my second
study, by probing the in vivo gene expression program with mathematical modeling of in silico genes, I have
identified that the innate immune response gene activation program is simply composed of three major
transcriptional pathways rather than 17 combinatorial gene regulatory pathways if we consider all possible
combinatorial control. Furthermore, I did not observe transcriptional synergy between the three major pathways,
instead, a novel class of regulation was identified, a synergistic AND gate between transcriptional regulation
and regulated mRNA half live control. I was also involved in studies lead by Dr. Chris Glass and Dr. Steven
Smale’s lab that characterized the underlying mechanism of innate immune response gene regulation at the
chromatin and epigenetic level.
1. Cheng CS, Feldman KE, Lee J, Verma S, Huang DB, Huynh K, Chang M, Ponomarenko JC, Sun SC,
Benedict CA, Ghosh G, Hoffmann A. The specificity of innate immune responses is enforced by
B p50. Science Signaling. 2011 Feb 22;4(161):ra11.
PMCID: PMC3096068 (Contributions: conceived study, designed/performed experiments and
computational analysis, wrote manuscript)
2. Cheng CS*, Behar M*, Suryawanshi GW, Feldman KE, Spreafico R, Hoffmann A. The combinatorial
control logic underlying pathogen-responsive gene expression programs involves sequential rather than
coincident molecular mechanisms. Submitted to Cell Systems, accepted for publication. (Contributions:
conceived study, designed/performed experiments and computational analysis, wrote manuscript)
3. Escoubet-Lozach L, Benner C, Kaikkonen MU, Lozach J, Heinz S, Spann NJ, Crotti A, Stender J,
Ghisletti S, Reichart D, Cheng CS, Luna R, Ludka C, Sasik R, Garcia-Bassets I, Hoffmann A,
Subramaniam S, Hardiman G, Rosenfeld MG, Glass CK. Mechanisms establishing TLR4-responsive
activation states of inflammatory response genes. PLoS Genet. 2011 Dec;7(12):e1002401. PMCID:
PMC3234212 (Contribution: designed and performed experiments)
4. Ramirez-Carrozzi VR, Braas D, Bhatt DM, Cheng CS, Hong C, Doty KR, Black JC, Hoffmann A,
Carey M, Smale ST. A unifying model for the selective regulation of inducible transcription by CpG
islands and nucleosome remodeling. Cell. 2009 Jul 10;138(1):114-28. PMCID: PMC2712736
(Contribution: designed and performed computational analysis)
2. Development of various ChIP-seq based technologies
The recent development of a semiconductor-based, non-optical DNA sequencing technology promises scalable,
low-cost and rapid sequence data production. The technology has previously been applied mainly to genomic
sequencing and targeted re-sequencing. As a postdoctoral fellow in Aviv Regev’s laboratory at the Broad
Institute, I lead the development of a novel ChIP-seq library preparation method for the semiconductor-based
sequencing technology, Ion Torrent. We demonstrate the utility of Ion Torrent semiconductor-based sequencing
for sensitive, efficient and rapid chromatin immunoprecipitation followed by sequencing (ChIP-seq) through the
application of sample preparation methods that are optimized for ChIP-seq on the Ion Torrent platform. We
leverage this method for epigenetic profiling of tumour tissues. I was also involved in the development of a
high-throughput ChIP-seq approach that allows tens of ChIP-seq experiments to be performed at the same time
in a 96 well plate format with automated robotics. As a graduate student at UC San Diego, I was also involved
in the development of a Sensitive ChIP-DSL technology and I also help developed with computational analysis
of the resulted ChIP-seq data.
1. Cheng CS, Rai K, Garber M, Hollinger A, Robbins D, Anderson S, Macbeth A, Tzou A, Carneiro MO,
Raychowdhury R, Russ C, Hacohen N, Gershenwald JE, Lennon N, Nusbaum C, Chin L, Regev A,
Amit I. Semiconductor-based DNA sequencing of histone modification states. Nature
Communications. 2013;4:2672. (Contributions: conceived study, designed/performed experiments and
computational analysis, wrote manuscript)
2. Garber M, Yosef N, Goren A, Raychowdhury R, Thielke A, Guttman M, Robinson J, Minie B, Chevrier
N, Itzhaki Z, Blecher-Gonen R, Bornstein C, Amann-Zalcenstein D, Weiner A, Friedrich D, Meldrim J,
Ram O, Cheng C, Gnirke A, Fisher S, Friedman N, Wong B, Bernstein BE, Nusbaum C, Hacohen N,
Regev A, Amit I. A high-throughput chromatin immunoprecipitation approach reveals principles of
dynamic gene regulation in mammals. Mol Cell. 2012 Sep 14;47(5):810-22. PMCID: PMC3873101
(Contribution: designed and performed experiments)
3. Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, Ju BG, Ohgi KA, Wang J,
Escoubet-Lozach L, Rose DW, Glass CK, Fu XD, Rosenfeld MG. Histone methylation-dependent
mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell. 2007 Feb
9;128(3):505-18. PMCID: PMC1994663 (Contribution: designed and performed computational
analysis)
4. Kwon YS, Garcia-Bassets I, Hutt KR, Cheng CS, Jin M, Liu D, Benner C, Wang D, Ye Z, Bibikova M,
Fan JB, Duan L, Glass CK, Rosenfeld MG, Fu XD. Sensitive ChIP-DSL technology reveals an
extensive estrogen receptor alpha-binding program on human gene promoters. Proc Natl Acad Sci U S
A. 2007 Mar 20;104(12):4852-7. PMCID: PMC1821125 (Contribution: designed and performed
computational analysis)
3. Utilizing variability between individual humans to identify gene variants that are associated with the
variability in chromatin accessibility in activated primary human T cells
As a postdoctoral fellow in Aviv Regev’s laboratory at the Broad Institute, I utilized epigenetic variability
between individual humans as a perturbation tool to dissect transcriptional regulatory network. The vast
majority of genetic variants associated with complex human traits map to non-coding and gene regulatory
regions, but little is understood about how such genetic variants modulate gene regulation in health and disease.
Utilizing a recently available assay, Assay for Transposase-Accessible Chromatin (ATAC-seq) for fast and
sensitive epigenomic profiling of open chromatin, we performed ATAC-seq and RNA-seq in activated human
CD4+ T cells from 100 healthy individuals to identify ATAC-QTLs: genetic variants associated with variability
in chromatin accessibility. We found that ATAC-QTLs are widespread, disrupt binding sites for known
transcription factors important for CD4+ T cell differentiation and activation, overlap and mediate expression
QTLs from the same cells and are enriched for SNPs associated with autoimmune diseases. Measuring 3D
chromosome organization in primary CD4+ T cells by in situ-Hi-C, we further show that ATAC-QTLs can
simultaneously impact “multi-peaks” – multiple correlated open chromatin regions – and that such multi-peaks
tend to reside in the same chromatin contact domains and are enriched in super enhancers. Thus, variability in
chromatin accessibility in primary CD4+ T cells is heritable, determined by genetic variation in a manner
affected by the 3D organization of the genome, and mediates genetic effects on gene expression variation. Our
results provide insights into how genetic variants modulate chromatin state and gene expression in primary
immune cells that play a key role in many human diseases.
1.
Cheng CS*, Gate RE*, Aiden AP, Siba A, Tabaka M, Lituiev D, Machol I, Subramaniam M, MShamim
M4, Hougen KL, Wortman I, Huang SC, Durand NC, Feng T, De Jager PL, Chang HY, Lieberman
Aiden E, Benoist C, Beer MA, Ye CJ§, Regev A§. Genetic determinants of chromatin accessibility and
gene regulation in T cell activation across human individuals. Submitted to Science, in review.
(Contributions: conceived study, designed/performed experiments and computational analysis, wrote
manuscript)
4. Utilizing variability between individual cells to dissect transcriptional regulatory network in innate
immune response
Complex behaviors in multicellular organisms result from the cooperation of functionally specialized cell types.
However, deconvolution of cell mixtures into distinct subpopulations can be challenging due to a lack of, or
promiscuous, expression of specific cell surface markers. In my second project, I performed single cell ATACseq over 2000 single cells to discover de novo cell state classifications in resting and pathogen-stimulated DCs.
We find significant variation in chromatin accessibility, which can be systematically linked to the activity of
specific trans-factors and cis-elements in individual cells. Integrative analysis with single cell RNA-seq, multiparameter flow cytometry, and gene editing knockout studies allowed for the validation of three de novodefined developmental cell states with functionally distinct responses to identical pathogen stimuli.
Furthermore, we found intra-cell type variance characterized by activation state heterogeneity even in resting
cells. A small subset of resting DCs displayed ‘precocious’ anti-viral enhancers, driven by interferon response
factor 3 activity, which resulted in early response to pathogen stimulation. This study highlights principles of
cell-type specific networks underlying complex cellular behaviors - and the ability to interrogate these states
‘bottom-up’ using single cell epigenomic profiling.
1. Cheng CS*, Satpathy A*, Buenrostro JD*, Tabaka M*, Wortman I, Gennert D, Greenleaf WJ, Chang
HY§, Regev A§. Single-cell chromatin states reveal dynamic transcription factor control priming
pathogen response. In preparation. (Contributions: conceived study, designed/performed experiments
and designed computational analysis, wrote manuscript)
Complete list of Published Work in MyBibliography:
https://www.ncbi.nlm.nih.gov/sites/myncbi/christine.cheng.1/bibliography/45392763/public/?sort=date&directi
on=ascending
D. Research Support
Ongoing Research Support
Department of Biology, Boston University, New Faculty Startup Fund
Role: PI
Completed Research Support
None.
Cheng (PI)
09/01/16-08/31/19
$1,100,000