Chemical evidence suggests ritual use of psychoactive plants used to brew ayahuasca in pre-Columbian Bolivia.
Image courtesy of Juan Albarracin-Jordan and José M. Capriles.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Contributed by X. Sunney Xie, November 19, 2013 (sent for review November 11, 2013)
Significance
In mammals, the sense of odors relies on the peculiar expression pattern of olfactory receptors (ORs). Each single neuron chooses one, and only one, from all ∼1,400 OR genes that are present in a mouse genome. In neurobiology, a long-standing mystery is how such singularity can be achieved. We show theoretically that a simple kinetic scheme of OR activation followed by feedback can be solely responsible for the observed singularity, as long as the two timescales—slow activation by epigenetic modification and fast feedback by transcriptional regulation—are well separated. Our work provides the theoretical underpinning behind the choice of ORs, and demonstrates how the nervous system utilizes the kinetics of epigenetic changes to direct neurogenesis.
Abstract
Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (∼1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5–10 d—a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression.
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: chenghang.zong{at}bcm.edu or xie{at}chemistry.harvard.edu.
Author contributions: L.T., C.Z., and X.S.X. designed research; L.T. performed research; and L.T., C.Z., and X.S.X. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1321511111/-/DCSupplemental.
- aDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; and
- bDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
Contributed by X. Sunney Xie, November 19, 2013 (sent for review November 11, 2013)
Significance
In mammals, the sense of odors relies on the peculiar expression pattern of olfactory receptors (ORs). Each single neuron chooses one, and only one, from all ∼1,400 OR genes that are present in a mouse genome. In neurobiology, a long-standing mystery is how such singularity can be achieved. We show theoretically that a simple kinetic scheme of OR activation followed by feedback can be solely responsible for the observed singularity, as long as the two timescales—slow activation by epigenetic modification and fast feedback by transcriptional regulation—are well separated. Our work provides the theoretical underpinning behind the choice of ORs, and demonstrates how the nervous system utilizes the kinetics of epigenetic changes to direct neurogenesis.
Abstract
Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (∼1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5–10 d—a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression.
- neurogenesis
- stochastic gene expression
- histone modification
- kinetics modeling
- negative feedback
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: chenghang.zong{at}bcm.edu or xie{at}chemistry.harvard.edu.
Author contributions: L.T., C.Z., and X.S.X. designed research; L.T. performed research; and L.T., C.Z., and X.S.X. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1321511111/-/DCSupplemental.
Epigenetics initiates singular OR expression
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Researchers present evidence of Neolithic kinship and violence based on remains from a mass grave in Poland.
Image courtesy of Piotr Włodarczak.
Volume of cosmonauts’ brain ventricles increased by an average of 12% after spaceflight—a potential mechanism to cope with increased brain fluid volume, a study suggests.
Image courtesy of R. Maxine Rühl.
PNAS Profile of NAS member and cell biologist Junying Yuan
Image courtesy of Aaron Washington for Harvard Medical School.
The planned DUNE experiment, located in a cavern deep inside a defunct South Dakota gold mine, aims to do nothing less than probe the origins of matter.
Image credit: CERN.