Enhancer Interaction Networks as a Means for Singular Olfactory Receptor Expression
Open accessAbstract
The transcriptional activation of one out of ?2800 olfactory receptor (OR) alleles is a poorly understood process. Here, we identify a plethora of putative OR enhancers and study their in vivo activity in olfactory neurons. Distinguished by an unusual epigenetic signature, candidate OR enhancers are characterized by extensive interchromosomal interactions associated with OR transcription and share a similar pattern of transcription factor footprints. In particular, we establish the role of the transcription factor Bptf as a facilitator of both enhancer interactions and OR transcription. Our observations agree with the model whereby OR transcription occurs in the context of multiple interacting enhancers. Disruption of these interchromosomal interactions results in weak and multigenic OR expression, suggesting that the rare coincidence of numerous enhancers over a stochastically chosen OR may account for the singularity and robustness in OR transcription.
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In an enhancer chain, not all enhancers need to contact the gene promoter directly; the signal could be passed along the chain.
“In this mechanism, not all of the enhancers need to contact the gene promoter directly; rather, the signal could be passed along the chain.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [488]
The Results section, “Extensive cis and trans interactions between potential OR enhancers in OSNs” (page unavailable), reports frequent enhancer–enhancer contacts, and the Discussion proposes that multiple enhancers contribute to OR transcription. The paper does not establish or explicitly propose that a signal passes along an enhancer chain so that some enhancers need not contact the promoter directly. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThere is evidence for enhancer-enhancer interactions that create an enhancer chain or network.
“there is also evidence for enhancer–enhancer interactions that create an enhancer “chain” or network [486–489].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [488]
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References 65 · Cited by 214
Research works printed but not linked: 52
- Andrey G Duboule D SnapShot: Hox gene regulation. Cell 2014 156 856 856 e851 24529385
- Apostolou E Thanos D Virus Infection Induces NF-kappaB-dependent interchromosomal associations mediating monoallelic IFN-beta gene expression. Cell 2008 134 85 96 18614013
- Ariza-Cosano A Visel A Pennacchio LA Fraser HB Gomez-Skarmeta JL Irimia M Bessa J Differences in enhancer activity in mouse and zebrafish reporter assays are often associated with changes in gene expression. BMC Genomics 2012 13 713 23253453 PMC3541358
- Armelin-Correa LM Gutiyama LM Brandt DY Malnic B Nuclear compartmentalization of odorant receptor genes. Proceedings of the National Academy of Sciences of the United States of America 2014 111 2782 2787 24550308 PMC3932893
- Bailey TL Elkan C Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proceedings / International Conference on Intelligent Systems for Molecular Biology; ISMB International Conference on Intelligent Systems for Molecular Biology 1994 2 28 36 7584402
- Bargmann CI Comparative chemosensation from receptors to ecology. Nature 2006 444 295 301 17108953
- Barnea G O'Donnell S Mancia F Sun X Nemes A Mendelsohn M Axel R Odorant receptors on axon termini in the brain. Science (New York, NY 2004 304 1468 15178793
- Bonn S Zinzen RP Girardot C Gustafson EH Perez-Gonzalez A Delhomme N Ghavi-Helm Y Wilczynski B Riddell A Furlong EE Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nature genetics 2012 44 148 156 22231485
- Booker BM Murphy KK Ahituv N Functional analysis of limb enhancers in the developing fin. Development genes and evolution 2013 223 395 399 24068387 PMC3869458
- Bushdid C Magnasco MO Vosshall LB Keller A Humans can discriminate more than 1 trillion olfactory stimuli. Science (New York, NY 2014 343 1370 1372 PMC4483192 24653035
- Chess A Simon I Cedar H Axel R Allelic inactivation regulates olfactory receptor gene expression. Cell 1994 78 823 834 8087849
- Clowney EJ LeGros MA Mosley CP Clowney FG Markenskoff-Papadimitriou EC Myllys M Barnea G Larabell CA Lomvardas S Nuclear aggregation of olfactory receptor genes governs their monogenic expression. Cell 2012 151 724 737 23141535 PMC3659163
- Clowney EJ Magklara A Colquitt BM Pathak N Lane RP Lomvardas S High-throughput mapping of the promoters of the mouse olfactory receptor genes reveals a new type of mammalian promoter and provides insight into olfactory receptor gene regulation. Genome research 2011 21 1249 1259 21705439 PMC3149492
- Dalton RP Lyons DB Lomvardas S Co-opting the unfolded protein response to elicit olfactory receptor feedback. Cell 2013 155 321 332 24120133 PMC3843319
- Delpretti S Montavon T Leleu M Joye E Tzika A Milinkovitch M Duboule D Multiple enhancers regulate Hoxd genes and the Hotdog LncRNA during cecum budding. Cell reports 2013 5 137 150 24075990
- Ernst J Kheradpour P Mikkelsen TS Shoresh N Ward LD Epstein CB Zhang X Wang L Issner R Coyne M Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 2011 473 43 49 21441907 PMC3088773
- Ferreira T Wilson SR Choi YG Risso D Dudoit S Speed TP Ngai J Silencing of Odorant Receptor Genes by G Protein betagamma Signaling Ensures the Expression of One Odorant Receptor per Olfactory Sensory Neuron. Neuron 2014 81 847 859 24559675 PMC4412037
- Hebert JM McConnell SK Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Developmental biology 2000 222 296 306 10837119
- Hirota J Mombaerts P The LIM-homeodomain protein Lhx2 is required for complete development of mouse olfactory sensory neurons. Proceedings of the National Academy of Sciences of the United States of America 2004 101 8751 8755 15173589 PMC423267
- Johnston RJ Jr. Desplan C Interchromosomal communication coordinates intrinsically stochastic expression between alleles. Science (New York, NY 2014 343 661 665 PMC4134473 24503853
- Jordan-Sciutto KL Dragich JM Rhodes JL Bowser R Fetal Alz-50 clone 1, a novel zinc finger protein, binds a specific DNA sequence and acts as a transcriptional regulator. The Journal of biological chemistry 1999 274 35262 35268 10575013 PMC3670955
- Khan M Vaes E Mombaerts P Regulation of the probability of mouse odorant receptor gene choice. Cell 2011 147 907 921 22078886
- Kothary R Clapoff S Brown A Campbell R Peterson A Rossant J A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube. Nature 1988 335 435 437 3138544
- Krzywinski M Schein J Birol I Connors J Gascoyne R Horsman D Jones SJ Marra MA Circos: an information aesthetic for comparative genomics. Genome research 2009 19 1639 1645 19541911 PMC2752132
- Landry JW Banerjee S Taylor B Aplan PD Singer A Wu C Chromatin remodeling complex NURF regulates thymocyte maturation. Genes & development 2011 25 275 286 21289071 PMC3034902
- Lewcock JW Reed RR A feedback mechanism regulates monoallelic odorant receptor expression. Proceedings of the National Academy of Sciences of the United States of America 2004 101 1069 1074 14732684 PMC327152
- Li Q Ritter D Yang N Dong Z Li H Chuang JH Guo S A systematic approach to identify functional motifs within vertebrate developmental enhancers. Developmental biology 2010 337 484 495 19850031 PMC3330829
- Lomvardas S Barnea G Pisapia DJ Mendelsohn M Kirkland J Axel R Interchromosomal interactions and olfactory receptor choice. Cell 2006 126 403 413 16873069
- Lyons DB Allen WE Goh T Tsai L Barnea G Lomvardas S An epigenetic trap stabilizes singular olfactory receptor expression. Cell 2013 154 325 336 23870122 PMC3929589
- Magklara A Yen A Colquitt BM Clowney EJ Allen W Markenscoff-Papadimitriou E Evans ZA Kheradpour P Mountoufaris G Carey C An epigenetic signature for monoallelic olfactory receptor expression. Cell 2011 145 555 570 21529909 PMC3094500
- McGaughey DM Vinton RM Huynh J Al-Saif A Beer MA McCallion AS Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b. Genome research 2008 18 252 260 18071029 PMC2203623
- Montavon T Soshnikova N Mascrez B Joye E Thevenet L Splinter E de Laat W Spitz F Duboule D A regulatory archipelago controls Hox genes transcription in digits. Cell 2011 147 1132 1145 22118467
- Navarro M Gull K A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Nature 2001 414 759 763 11742402
- Neph S Stergachis AB Reynolds A Sandstrom R Borenstein E Stamatoyannopoulos JA Circuitry and dynamics of human transcription factor regulatory networks. Cell 2012a 150 1274 1286 22959076 PMC3679407
- Neph S Vierstra J Stergachis AB Reynolds AP Haugen E Vernot B Thurman RE John S Sandstrom R Johnson AK An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 2012b 489 83 90 22955618 PMC3736582
- Nishizumi H Kumasaka K Inoue N Nakashima A Sakano H Deletion of the core-H region in mice abolishes the expression of three proximal odorant receptor genes in cis. Proceedings of the National Academy of Sciences of the United States of America 2007 104 20067 20072 18077433 PMC2148423
- Nolis IK McKay DJ Mantouvalou E Lomvardas S Merika M Thanos D Transcription factors mediate long-range enhancer-promoter interactions. Proceedings of the National Academy of Sciences of the United States of America 2009 106 20222 20227 19923429 PMC2779200
- Noordermeer D Leleu M Schorderet P Joye E Chabaud F Duboule D Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci. eLife 2014 3 e02557 24843030 PMC4017647
- Ribich S Tasic B Maniatis T Identification of long-range regulatory elements in the protocadherin-alpha gene cluster. Proceedings of the National Academy of Sciences of the United States of America 2006 103 19719 19724 17172445 PMC1750919
- Rothman A Feinstein P Hirota J Mombaerts P The promoter of the mouse odorant receptor gene M71. Molecular and cellular neurosciences 2005 28 535 546 15737743
- Ruthenburg AJ Li H Milne TA Dewell S McGinty RK Yuen M Ueberheide B Dou Y Muir TW Patel DJ Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 2011 145 692 706 21596426 PMC3135172
- Serizawa S Miyamichi K Nakatani H Suzuki M Saito M Yoshihara Y Sakano H Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse. Science (New York, NY 2003 302 2088 2094 14593185
- Shykind BM Rohani SC O'Donnell S Nemes A Mendelsohn M Sun Y Axel R Barnea G Gene switching and the stability of odorant receptor gene choice. Cell 2004 117 801 815 15186780
- Stergachis AB Haugen E Shafer A Fu W Vernot B Reynolds A Raubitschek A Ziegler S LeProust EM Akey JM Exonic transcription factor binding directs codon choice and affects protein evolution. Science (New York, NY 2013 342 1367 1372 PMC3967546 24337295
- Sullivan SL Adamson MC Ressler KJ Kozak CA Buck LB The chromosomal distribution of mouse odorant receptor genes. Proceedings of the National Academy of Sciences of the United States of America 1996 93 884 888 8570653 PMC40152
- Vassalli A Feinstein P Mombaerts P Homeodomain binding motifs modulate the probability of odorant receptor gene choice in transgenic mice. Molecular and cellular neurosciences 2011 46 381 396 21111823 PMC3746036
- Wang F Nemes A Mendelsohn M Axel R Odorant receptors govern the formation of a precise topographic map. Cell 1998 93 47 60 9546391
- Williams A Spilianakis CG Flavell RA Interchromosomal association and gene regulation in trans. Trends Genet 2010 26 188 197 20236724 PMC2865229
- Wysocka J Swigut T Xiao H Milne TA Kwon SY Landry J Kauer M Tackett AJ Chait BT Badenhorst P A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 2006 442 86 90 16728976
- Zang C Schones DE Zeng C Cui K Zhao K Peng W A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 2009 25 1952 1958 19505939 PMC2732366
- Zhang X Rodriguez I Mombaerts P Firestein S Odorant and vomeronasal receptor genes in two mouse genome assemblies. Genomics 2004 83 802 811 15081110
- Zhou Z Belluscio L Coding odorant concentration through activation timing between the medial and lateral olfactory bulb. Cell reports 2012 2 1143 1150 23168258 PMC3513620
- Authors
- Markenscoff-Papadimitriou, E., Allen, W. E., Colquitt, B. M., Goh, T., Murphy, K. K., Monahan, K., Mosley, C. P., Ahituv, N., & Lomvardas, S.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- Corresponding author
- Lomvardas, Stavros
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 159
- Issue
- 3
- Pages
- 543-557
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4243057
- OpenAlex
- W1970956961
- Cited by
- 214
- References
- 65
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 16 · 2023: 20 · 2022: 14 · 2021: 24 · 2020: 21 · 2019: 26 · 2018: 19 · 2017: 17 · 2016: 14 · 2015: 16 · 2014: 1
- FWCI
- 6.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01DA036985, R01DA030320, R01DA036894)
- National Institute on Deafness and Other Communication Disorders (R01DC013560)
- National Institute of General Medical Sciences (P30GM138441)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090382)
- National Institute of Neurological Disorders and Stroke (R01NS079231)
- National Center for Research Resources (P41RR019664)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- olfactory receptor genes, enhancer interactions, interchromosomal interactions, BPTF, transcription factor footprints, epigenetic signatures, olfactory sensory neurons, transcriptional activation
- MeSH terms
- Bromodomain Containing Proteins, Animals, Enhancer Elements, Genetic, Nerve Tissue Proteins, Nucleoproteins, Transcription Factors, Zebrafish, Transcriptional Activation, Olfactory Receptor Neurons, Receptors, Odorant, Animals, Genetically Modified, Antigens, Nuclear, Mice
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