2017 NIH SCAP-T: Is heterogeneity regulated?

(Stephen Fisher) #1

Thurs, June 29th, Breakout Session

Moderator: Suraj Bhat, Ph.D. (University of California Los Angeles)

The heterogeneity of gene expression in single cells is well established however it is unclear if this heterogeneity has any relationship to the morphological and/or molecular phenotype of a tissue or an organ. In this session we will ask questions to elucidate the challenges, both technical as well as conceptual, in understanding the role of the cellular variability (as assessed by gene expression) in the context of multicellularity of tissues and organs. We will explore the possible role of cellular heterogeneity in terminal differentiation. At the current state of our knowledge, we do not have a handle on whether the variation in the abundance of a gene transcript from cell to cell is because of the fluctuations intrinsic to the gene activity or whether it is the other cellular components that determine the variability between cells. In either case the question remains – what is regulated?

Some of the questions that we will address (not necessarily in the order listed):

  • Is heterogeneity causal or a result of the gene activity?
  • Is heterogeneity functional?
  • What is the relationship between the tissue /organ phenotype to the single cell?
  • Is heterogeneity the pathway to terminal differentiation?
  • Do different developmental programs entail specific states (stages) of heterogeneity?
  • What are the deterministic sources of cellular variability and how are they maintained?
  • Is deterministic variability important and what purpose does it serve?
  • Do we understand the link between molecular variability and the phenotypic variability between individual cells? (Technically how do we study heterogeneity in single cells?)

(Pawel Osmulski) #2

Another issue - the role of stochastic state transitions in phenotypic equilibrium of populations of canceer cells

(John Tsang) #3

These are great questions. We recently started exploring some of these by utilizing the inherent subject-to-subject variation in protein expression heterogeneity in immune cell subpopulations in a human cohort (see references below).



Abstract: Cell-to-cell expression variation (CEV) is a prevalent feature of even well-defined cell populations, but its functions, particularly at the organismal level, are not well understood. Using single-cell data obtained via high-dimensional flow cytometry of T cells as a model, we introduce an analysis framework for quantifying CEV in primary cell populations and studying its functional associations in human cohorts. Analyses of 840 CEV phenotypes spanning multiple baseline measurements of 14 proteins in 28 T cell subpopulations suggest that the quantitative extent of CEV can exhibit substantial subject-to-subject differences and yet remain stable within healthy individuals over months. We linked CEV to age and disease-associated genetic polymorphisms, thus implicating CEV as a biomarker of aging and disease susceptibility and suggesting that it might play an important role in health and disease. Our dataset, interactive figures, and software for computing CEV with flow cytometry data provide a resource for exploring CEV functions.

John Tsang
Laboratory of Systems Biology and Trans-NIH Center for Human Immunology

(Terence Shine) #4

There’s no bigger issue as far as I’m concerned.

(Terence Shine) #5

Great references. Especially with the protein heterogeneity stuff.