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2016 ; 12
(8
): e1005072
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Determining Physical Mechanisms of Gene Expression Regulation from Single Cell
Gene Expression Data
#MMPMID27551778
Ezer D
; Moignard V
; Göttgens B
; Adryan B
PLoS Comput Biol
2016[Aug]; 12
(8
): e1005072
PMID27551778
show ga
Many genes are expressed in bursts, which can contribute to cell-to-cell
heterogeneity. It is now possible to measure this heterogeneity with high
throughput single cell gene expression assays (single cell qPCR and RNA-seq).
These experimental approaches generate gene expression distributions which can be
used to estimate the kinetic parameters of gene expression bursting, namely the
rate that genes turn on, the rate that genes turn off, and the rate of
transcription. We construct a complete pipeline for the analysis of single cell
qPCR data that uses the mathematics behind bursty expression to develop more
accurate and robust algorithms for analyzing the origin of heterogeneity in
experimental samples, specifically an algorithm for clustering cells by their
bursting behavior (Simulated Annealing for Bursty Expression Clustering, SABEC)
and a statistical tool for comparing the kinetic parameters of bursty expression
across populations of cells (Estimation of Parameter changes in Kinetics, EPiK).
We applied these methods to hematopoiesis, including a new single cell dataset in
which transcription factors (TFs) involved in the earliest branchpoint of blood
differentiation were individually up- and down-regulated. We could identify two
unique sub-populations within a seemingly homogenous group of hematopoietic stem
cells. In addition, we could predict regulatory mechanisms controlling the
expression levels of eighteen key hematopoietic transcription factors throughout
differentiation. Detailed information about gene regulatory mechanisms can
therefore be obtained simply from high throughput single cell gene expression
data, which should be widely applicable given the rapid expansion of single cell
genomics.