Nucleosomes are preferentially positioned at exons in somatic and sperm cells
Open accessAbstract
Nucleosome positioning is constrained at eukaryotic transcription start sites and implicated in transcriptional regulation. Moreover, recent observations indicate that chromatin structure, transcription and splicing are functionally intertwined, and that modified nucleosomes with trimethylation of lysine 36 in histone subunit 3 (H3K36me3) are enriched at internal exons and the downstream flanking intronic regions of highly expressed genes. However, the position of nucleosomes in the interior of genes has been thought to be largely random. Here we show, by analysis of data sets from human sperm and T cells and medaka (Japanese killifish, Oryzias latipes) blastulae, that internal exons of genes are characterized by sharply elevated average nucleosome occupancy in comparison to flanking intronic sequences. We also show that the preferential positioning of nucleosomes at internal exons is independent of their modification status, and of the GC content, conservation or the expression level of the exon. These findings show that the location of exons is recorded in the chromatin structure and may be inherited across generations. Such embedded information may underpin transcriptionally coupled exon recognition and splice site selection.
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Increased nucleosome occupancy occurs on exons with respect to introns.
“First, increased nucleosome occupancy occurs on exons with respect to introns (Andersson et al, 2009; Nahkuri et al, 2009; Schwartz et al, 2009; Spies et al, 2009; Tilgner et al, 2009; Chodavarapu et al, 2010).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Nahkuri et al, 2009
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ResultWhere splicing joins chromatin
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BackgroundDesign principles of interconnections between chromatin and pre-mRNA splicing
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BackgroundA diverse epigenetic landscape at human exons with implication for expression
Singer, M., Kosti, I., Pachter, L. S., & Mandel‐Gutfreund, Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv153 · Cited by 50 · see citing works
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“In 2009, an avalanche of articles based on genome-wide analyses, demonstrated that nucleosomes are preferentially positioned in exons (Andersson et al. 2009; Hon et al. 2009; Nahkuri et al. 2009; Schwartz et al. 2009; Spies et al. 2009; Tilgner et al. 2009).”
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“…are enriched in exons over introns, suggesting that exons represent regions of more stable nucleosome occupancy (positioning), a phenomenon that appears to be evolutionarily conserved (Hodges et al. 2009; Nahkuri et al. 2009; Schwartz et al. 2009; Spies et al. 2009; Tilgner et al. 2009) (Fig.”
BackgroundPre-mRNA splicing: Role of epigenetics and implications in disease
Khan, D. H., Jahan, S., & Davie, J. (2012) · Advances in Biological Regulation · doi:10.1016/j.jbior.2012.04.003 · Cited by 41 · see citing works
“All rights reserved.”
Ponts, N., Harris, E. Y., Lonardi, S., & Roch, K. G. L. (2010) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2010.08.002 · Cited by 39 · see citing works
“We also found that nucleosomes are mostly localized within exons, consistent with other observations in human and yeast (Nahkuri et al., 2009; Schwartz et al., 2009; Tilgner et al., 2009; Andersson et al., 2009).”
ResultYazdi, P. G., Pedersen, B., Taylor, J. F., Khattab, O. S., Chen, Y., Chen, Y., Jacobsen, S. E., & Wang, P. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136574 · Cited by 34 · see citing works
“Second, it is well known that coding regions have higher nucleosome occupancy than non-coding regions[54, 55].”
BackgroundRegulated pre-mRNA splicing: The ghostwriter of the eukaryotic genome
Johnson, T., & Vilardell, J. (2012) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.12.011 · Cited by 34 · see citing works
“Analysis of genome-wide surveys from Drosophila and mammals have revealed that nucleosomes and, according to several of these studies, specific histone modifications are enriched in exon sequences, suggesting that there may be specific histone “marks” that are associated with splicing [23-29].”
Pre‐mRNA splicing during transcription in the mammalian system
Pandya‐Jones, A. (2011) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.86 · Cited by 33 · see citing works
Promoter-like epigenetic signatures in exons displaying cell type-specific splicing
Curado, J., Iannone, C., Tilgner, H., Valcárcel, J., & Guigó, R. (2015) · Genome biology · doi:10.1186/s13059-015-0797-8 · Cited by 31 · see citing works
“Lastly, a number of independent studies demonstrated that nucleosome density correlates with exon-intron architecture genome-wide [9, 14–19], and specifically with exon inclusion levels [20, 21].”
BackgroundRNA Polymerase II Elongation at the Crossroads of Transcription and Alternative Splicing
de la Mata, M., Muñoz, M. J., Alló, M., Fededa, J. P., Schor, I. E., & Kornblihtt, A. R. (2011) · Genetics Research International · doi:10.4061/2011/309865 · Cited by 30 · see citing works
“Notably, the average size of a mammalian exon is similar to the length of DNA wrapped around a nucleosome, suggesting a conserved function for the nucleosome in exon definition [79, 80, 82].”
BackgroundOh, J., Sanders, I., Chen, E. Z., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117471 · Cited by 25 · see citing works
“Some studies have shown that nucleosomes are preferentially placed at exons in cell genes [50].”
BackgroundIannone, C., Pohl, A., Papasaikas, P., Soronellas, D., Vicent, G. P., Beato, M., & Valcárcel, J. (2015) · PubMed Central · Cited by 25 · see citing works
Connecting the dots: chromatin and alternative splicing in EMT
Warns, J. A., Davie, J., & Dhasarathy, A. (2015) · Biochemistry and Cell Biology · doi:10.1139/bcb-2015-0053 · Cited by 24 · see citing works
“Studies based on genome-wide analyses demonstrated that nucleosomes are preferentially positioned in exons (Andersson et al. 2009; Hon et al. 2009; Nahkuri et al. 2009; Schwartz et al. 2009; Spies et al. 2009; Tilgner et al. 2009; Wilhelm et al. 2011; De Conti et al. 2013), and that this…”
BackgroundDiverse RNA interference strategies in early-branching metazoans
Calcino, A., Fernández-Valverde, S. L., Taft, R. J., & Degnan, B. M. (2018) · BMC Evolutionary Biology · doi:10.1186/s12862-018-1274-2 · Cited by 22 · see citing works
Self-citationThe central role of RNA in the genetic programming of complex organisms
Mattick, J. S. (2010) · Anais da Academia Brasileira de Ciências · doi:10.1590/s0001-37652010000400016 · Cited by 22 · see citing works
“In addition exons are preferentially associated with nucleosomes in somatic and sperm cells in vertebrates (Nahkuri et al. 2009), indicating that epigenetic regulation acts not just the level of the gene, but at the level of individual exons, which potentially explains the basis of the long-standing mystery of how alt…”
BackgroundSelf-citationSystems analysis of alternative splicing and its regulation
Xiao, X. G., & Lee, J. (2010) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.84 · Cited by 20 · see citing works
Histone H1.5 binds over splice sites in chromatin and regulates alternative splicing
Glaich, O., Leader, Y., Lev-Maor, G., & Ast, G. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz338 · Cited by 19 · see citing works
“]; Ministry of Science and Technology R&D IsraelGerman [3-13112]; Binational Science Foundation United States-Israel [BSF 2017086]; German-Israel foundation for R&D [GIF I-1460]; O.”
Mattick, J. S. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.11.001 · Cited by 17 · see citing works
Self-citationChromatin structure and pre-mRNA processing work together
Jimeno-González, S., & Reyes, J. C. (2016) · Transcription · doi:10.1080/21541264.2016.1168507 · Cited by 15 · see citing works
Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation
Pascal, C., Zonszain, J., Hameiri, O., Gargi-Levi, C., Lev-Maor, G., Tammer, L., Levy, T., Tarabeih, A., Roy, V. R., Ben-Salmon, S., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.10.003 · Cited by 17 · see citing works
The Functional Relationship Between RNA Splicing and the Chromatin Landscape
Yustis, J.-C., Devoucoux, M., & Côté, J. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168614 · Cited by 16 · see citing works
RNA driving the epigenetic bus
Mattick, J. S. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.479 · Cited by 16 · see citing works
“It has recently been discovered that nucleosomes are preferentially positioned over exons in both somatic and germ cells (Nahkuri et al , 2009), raising the prospect of the preprogrammed epigenetic control of splicing, which has since obtained experimental support (Luco et al , 2011).”
Self-citationJabre, I., Chaudhary, S., Wilson, C. M., Staiger, D., & Syed, N. H. (2022) · Plants · doi:10.3390/plants11091105 · Cited by 15 · see citing works
Choi, Y., & Mango, S. E. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.05.011 · Cited by 15 · see citing works
Human exonization through differential nucleosome occupancy
Li, Y., Li, C., Li, S., Peng, Q., An, N. A., He, A., & Li, C. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802561115 · Cited by 15 · see citing works
Gnan, S., Matelot, M., Weiman, M., Arnaiz, O., Guèrin, F., Sperling, L., Bétermier, M., Thermes, C., Chen, C.-L., & Duharcourt, S. (2022) · Genome Research · doi:10.1101/gr.276125.121 · Cited by 12 · see citing works
“…that nucleosomes are preferentially positioned in exons compared with introns in diverse organisms, including Schizosaccharomyces pombe , Drosophila , worms, and humans (Andersson et al. 2009; Nahkuri et al. 2009; Schwartz et al. 2009; Spies et al. 2009; Tilgner et al. 2009; Iannone et al. 2015).”
Dey, P., & Mattick, J. S. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00419-2 · Cited by 13 · see citing works
Self-citationImbriano, C., & Belluti, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158304 · Cited by 13 · see citing works
Alves, V. C., Figueiro‐Silva, J., Ferrer, I., & Carro, E. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04845-1 · Cited by 12 · see citing works
Chaudhary, S., Jabre, I., & Syed, N. H. (2021) · Genomics · doi:10.1016/j.ygeno.2021.08.006 · Cited by 11 · see citing works
“Furthermore, constitutive exons in both plants and animals show higher nucleosome occupancy levels compared to introns and alternative exons [26,31–37].”
BackgroundHu, W., Foord, C., Hsu, J., Fan, L., Corley, M. J., Lanjewar, S. N., Xu, S., Belchikov, N., He, Y., Pang, A. P. S., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02734-5 · Cited by 14 · see citing works
Untranslated Gene Regions and Other Non-coding Elements
Barrett, L. W., Fletcher, S., & Wilton, S. D. (2013) · SpringerBriefs in biochemistry and molecular biology · doi:10.1007/978-3-0348-0679-4_1 · Cited by 12 · see citing works
“As well as containing regulatory elements, introns are characterised by a significantly lower nucleosome density in comparison to exons (Nahkuri et al. 2009), and different histone modifications define exons, alternatively spliced exons, and introns (Dhami et al. 2010).”
BackgroundRNA as the substrate for epigenome‐environment interactions
Mattick, J. S. (2010) · BioEssays · doi:10.1002/bies.201090026 · Cited by 10 · see citing works
Self-citationHigh resolution positioning of intron ends on the nucleosomes
Hapala, J., & Trifonov, E. N. (2011) · Gene · doi:10.1016/j.gene.2011.08.022 · Cited by 8 · see citing works
Prohaska, S. J., & Stadler, P. F. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-027-0_8 · Cited by 8 · see citing works
“To date, it is known that histone marks can index the genome, marking transcribed regions, active promoters, direction of transcription, and exon/intron boundaries [2, 49, 66, 71].”
BackgroundHow do RNA sequence, DNA sequence, and chromatin properties regulate splicing?
Ringrose, L. (2010) · F1000 Biology Reports · doi:10.3410/b2-74 · Cited by 7 · see citing works
“The preference of nucleosomes for exons appears to be a consequence not only of the higher guanine and cytosine content of exons [38,39,41] but also of a high density of sequences that repel nucleosomes [6] exactly at the intron-exon boundary and a depletion of these sequences within the exon itself relative to the ad…”
BackgroundInfluentialHuman Transcriptome and Chromatin Modifications: An ENCODE Perspective
Shen, L., Choi, I., Nestler, E. J., & Won, K. (2013) · Genomics & Informatics · doi:10.5808/gi.2013.11.2.60 · Cited by 4 · see citing works
“These observations confirm the idea that chromatin structure could play a role in splicing [7, 30-34].”
BackgroundMichielsen, L., Hsu, J., Joglekar, A., Belchikov, N., Reinders, M. J. T., Tilgner, H., & Mahfouz, A. E. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.18.585465 · Cited by 4 · see citing works
The Worlds of Splicing and Chromatin Collide
Adam, J., & Philippe, T. J. (2011) · InTech eBooks · doi:10.5772/19985 · Cited by 3 · see citing works
“Next-generation sequencing, using various technical platforms (IlluminaTM, Roche 454 sequencing, pyrosequencing), following microccocal nuclease (MNase) digestion of chromatin from various organisms and cell types, has allowed precise mapping of nucleosome distribution over the entire genome ([42]; [43]; [44]; [45]; […”
BackgroundMethodChromatin Remodelling and RNA Processing
Böhm, S., & Farrants, A. Ö. (2011) · InTech eBooks · doi:10.5772/20998 · Cited by 2 · see citing works
“…sequencing (presented in Schones et al., 2008) have shown that exons are more prone to harbour positioned nucleosomes than intronic regions (Tilgner et al., 2009; Schwartz et al., 2009: Andersson et al., 2009; Hon et al., 2009; Speis et al., 2009; Nahkuri et al., 2009; Chodavarapu et al., 2010).”
Distribution of Nucleosome-enriched Sequences of Human Sperm Chromatin Along Isochores
Arhondakis, S., & Varriale, A. (2018) · Exploratory Research and Hypothesis in Medicine · doi:10.14218/erhm.2018.00009 · Cited by 3 · see citing works
Zhang, M.-Z., Cao, X., Xu, F., et al. (2019) · Biology Open · doi:10.1242/bio.041368 · Cited by 3 · see citing works
Rapid Method of Processing Sperm for Nucleic Acid Extraction in Clinical Research
de Gannes, M. (2021) · ScholarWorks@UMassAmherst (University of Massachusetts Amherst) · doi:10.7275/5457102 · Cited by 3 · see citing works
Design Considerations for the Digital Core of a C1G2 RFID Tag
Zalbide, I., Juan, F., & Vlez, I. (2010) · InTech eBooks · doi:10.5772/7969 · Cited by 2 · see citing works
Pulmonary remodeling in asthma
Lieberman, P. (2010) · F1000 Medicine Reports · doi:10.3410/m2-74 · Cited by 1 · see citing works
Niu, D., & Cao, J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.046 · Cited by 1 · see citing works
“By analyzing nucleosome distribution across genes, researchers have recently found that nucleosomes are strongly enriched on exons, especially those flanked by long introns [18–24].”
BackgroundEpigenetic modifications and alternative pre-mRNA splicing in cancer
Yadav, P., Pandkar, M. R., & Shukla, S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823931-5.00011-6 · Cited by 1 · see citing works
RNA Networks as Digital Control Circuits of Nuclear Functions
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Self-citationDiverse RNA interference strategies in early-branching metazoansPreprint
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“Nucleosome not only plays a basic structural role, but also participates in regulation of many life processes, such as replication, transcription, and DNA repaired etc [4] [5] [6] [7] [8] [9] [10] [11] [12].”
BackgroundBabenko, V. N., Matvienko, V., & Zykov, I. A. (2012) · Russian Journal of Genetics Applied Research · doi:10.1134/s2079059712010029
Role of Epigenetic Factors in RNA Splicing
Chen, W. (2011)
Harper, L. V. (2013) · Advances in child development and behavior · doi:10.1016/b978-0-12-397947-6.00012-x
Interconnections between transcription and pre-mRNA splicing
Gonchar, O. (2016) · Figshare
Global analysis of alternative splicing in human cells of myeloid origin
Alberto, L. P. (2018) · doi:10.32657/10356/74234
“It has been shown that introns are practically almost devoid of nucleosomes, whereas exons are preferentially bound by nucleosomes (Andersson et al., 2009; Nahkuri et al., 2009).”
BackgroundGnan, S., Matelot, M., Weiman, M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.05.455221
Alves, V. C., Figueiro‐Silva, J., Ferrer, I., & Carro, E. (2021) · Research Square · doi:10.21203/rs.3.rs-1098461/v1
Optical Beam Steering Using a 2D MEMS Scanner
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Andersson, R. (2010) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
- Authors
- Nahkuri, S., Taft, R. J., & Mattick, J. S.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Mattick, John S.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-10-15
- Volume
- 8
- Issue
- 20
- Pages
- 3420-3424
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W1972439760
- Cited by
- 106
- References
- 32
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 6 · 2019: 3 · 2018: 6 · 2016: 3 · 2015: 8 · 2014: 2 · 2013: 7 · 2012: 12
- FWCI
- 7.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- University of Queensland
- Suomen Kulttuurirahasto
- Queensland Government
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- nucleosome positioning, introns, nucleosome occupancy, chromatin structure, transcription start sites, T cells, exon recognition, splice site selection, GC content
- MeSH terms
- Animals, Chromatin, Exons, Histones, Humans, Male, Nucleosomes, Oryzias, Spermatozoa, T-Lymphocytes, RNA Splice Sites
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