Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice

Author:

Bashkirova Elizaveta V12,Klimpert Nell3ORCID,Monahan Kevin4,Campbell Christine E56,Osinski Jason56,Tan Longzhi7,Schieren Ira2,Pourmorady Ariel12,Stecky Beka2,Barnea Gilad3ORCID,Xie Xiaoliang Sunney89,Abdus-Saboor Ishmail2ORCID,Shykind Benjamin M10,Marlin Bianca J2ORCID,Gronostajski Richard M56,Fleischmann Alexander3ORCID,Lomvardas Stavros211ORCID

Affiliation:

1. Integrated Program in Cellular, Molecular and Biomedical Studies, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University

2. Zuckerman Mind, Brain, and Behavior Institute, Columbia University

3. Department of Neuroscience, Division of Biology and Medicine and Robert J. and Nancy D. Carney Institute for Brain Science, Brown University

4. Department of Biochemistry and Molecular Biology, Rutgers University

5. Department of Biochemistry, University at Buffalo and New York State Center of Excellence in Bioinformatics and Life Sciences

6. Genetics, Genomics, and Bioinformatics Graduate Program, University at Buffalo and New York State Center of Excellence in Bioinformatics and Life Sciences

7. Department of Bioengineering, Stanford University

8. Beijing Innovation Center for Genomics, Peking University

9. Biomedical Pioneering Innovation Center, Peking University

10. Prevail Therapeutics- a wholly-owned subsidiary of Eli Lilly and Company

11. Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University

Abstract

Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this ‘privileged’ repertoire. Our experiments identify early transcription as a potential ‘epigenetic’ contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.

Funder

National Institute on Deafness and Other Communication Disorders

Common Fund

New York State Stem Cell Science

The BRAIN Initiative

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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