Coregulation of Transcription Factor Binding and Nucleosome Occupancy through DNA Features of Mammalian Enhancers
Open accessAbstract
Transcription factors (TFs) preferentially bind sites contained in regions of computationally predicted high nucleosomal occupancy, suggesting that nucleosomes are gatekeepers of TF binding sites. However, because of their complexity mammalian genomes contain millions of randomly occurring, unbound TF consensus binding sites. We hypothesized that the information controlling nucleosome assembly may coincide with the information that enables TFs to bind cis-regulatory elements while ignoring randomly occurring sites. Hence, nucleosomes would selectively mask genomic sites that can be contacted by TFs and thus be potentially functional. The hematopoietic pioneer TF Pu.1 maintained nucleosome depletion at macrophage-specific enhancers that displayed a broad range of nucleosome occupancy in other cell types and in reconstituted chromatin. We identified a minimal set of DNA sequence and shape features that accurately predicted both Pu.1 binding and nucleosome occupancy genome-wide. These data reveal a basic organizational principle of mammalian cis-regulatory elements whereby TF recruitment and nucleosome deposition are controlled by overlapping DNA sequence features.
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PU.1 can bind as a pioneer factor that displaces nucleosomes to open sites for other factors.
“it is known to be able to bind either as a pioneer factor which displaces nucleosomes to open sites for other factors (12)”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [12]
The Results ('Selective masking of engaged Pu.1 sites by nucleosomes'; page unavailable) report that PU.1 binding in macrophages correlated with nucleosome removal or partial displacement and the formation of nucleosome-depleted regions. The Introduction explains that pioneer factors increase DNA accessibility for other factors, but the paper does not establish that PU.1 itself causes nucleosome displacement to open sites for those factors. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPU.1 has chromatin opening activity in B cells, can eject nucleosomes in macrophage lines, and causes rapid increases in ATAC accessibility at sites it occupies when introduced into Scid.adh.2C2 cells.
“This is consistent with PU.1's activity as a site-specific chromatin opening factor in B cells (96, 97), with the ability of PU.1 to eject nucleosomes from sites where it binds in macrophage lines (12), and with its ability to cause rapid increases in ATAC accessibility at the sites it occupies when introduced into Scid.adh.2C2 cells (85).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [12]
The Results section ('Selective masking of engaged Pu.1 sites by nucleosomes'; page unavailable) reports removal of a centrally positioned nucleosome at some Pu.1-bound sites, but only partial displacement and repositioning at others. The Introduction identifies the study system as primary mouse macrophages, not macrophage cell lines. The B-cell and Scid.adh.2C2 statements have separate citations and are not assessed here. (LLM, conf=0.87)
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References 61 · Cited by 209
Research works printed but not linked: 44
- Calo E Wysocka J Modification of enhancer chromatin: what, how, and why? Molecular cell 2013 49 825 837 23473601 PMC3857148
- Chang C-C Lin C-J LIBSVM: A library for support vector machines ACM Trans Intell Syst Technol 2011 2 1 27
- Charoensawan V Janga S Bulyk M Babu M Teichmann S DNA sequence preferences of transcriptional activators correlate more strongly than repressors with nucleosomes Molecular cell 2012 47 183 192 22841002 PMC3566590
- Creyghton MP Cheng AW Welstead GG Kooistra T Carey BW Steine EJ Hanna J Lodato MA Frampton GM Sharp PA Histone H3K27ac separates active from poised enhancers and predicts developmental state Proc Natl Acad Sci U S A 2011 107 21931 21936 21106759 PMC3003124
- Dror I Zhou T Mandel-Gutfreund Y Rohs R Covariation between homeodomain transcription factors and the shape of their DNA binding sites Nucleic Acids Research 2014 42 430 441 24078250 PMC3874178
- Drucker H Burges CJ Kaufman L Smola A Vapnik V Support vector regression machines Advances in neural information processing systems 1997 155 161
- Fenouil R Cauchy P Koch F Descostes N Cabeza J Innocenti C.n. Ferrier P Spicuglia S Gut M Gut I CpG islands and GC content dictate nucleosome depletion in a transcription-independent manner at mammalian promoters Genome research 2012 22 2399 2408 23100115 PMC3514669
- Flicek P Amode MR Barrell D Beal K Brent S Carvalho-Silva D Clapham P Coates G Fairley S Fitzgerald S Ensembl 2012 Nucleic acids research 2012 40 D84 90 22086963 PMC3245178
- Gaffney D McVicker G Pai A Fondufe-Mittendorf Y Lewellen N Michelini K Widom J Gilad Y Pritchard J Controls of nucleosome positioning in the human genome PLoS genetics 2012 8 PMC3499251 23166509
- Ghisletti S Barozzi I Mietton F Polletti S De Santa F Venturini E Gregory L Lonie L Chew A Wei CL Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages Immunity 2010 32 317 328 20206554
- Gordân R Shen N Dror I Zhou T Horton J Rohs R Bulyk ML Genomic regions flanking E-box binding sites influence DNA binding specificity of bHLH transcription factors through DNA shape Cell reports 2013 3 1093 1104 23562153 PMC3640701
- Heinz S Benner C Spann N Bertolino E Lin YC Laslo P Cheng JX Murre C Singh H Glass CK Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Mol Cell 2010 38 576 589 20513432 PMC2898526
- Ioshikhes I Albert I Zanton S Pugh B Nucleosome positions predicted through comparative genomics Nature Genetics 2006 38 1210 1215 16964265
- Kaplan N Moore I Fondufe-Mittendorf Y Gossett A Tillo D Field Y LeProust E Hughes T Lieb J Widom J The DNA-encoded nucleosome organization of a eukaryotic genome Nature 2009 458 362 366 19092803 PMC2658732
- Koch F Fenouil R Gut M Cauchy P Albert TK Zacarias-Cabeza J Spicuglia S de la Chapelle AL Heidemann M Hintermair C Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters Nat Struct Mol Biol 2011 18 956 963 21765417
- Langmead B Trapnell C Pop M Salzberg SL Ultrafast and memory-efficient alignment of short DNA sequences to the human genome Genome biology 2009 10 R25 19261174 PMC2690996
- Lichtinger M Ingram R Hannah R Müller D Clarke D Assi S Lie-A-Ling M Noailles L Vijayabaskar M Wu M RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis The EMBO journal 2012 31 4318 4333 23064151 PMC3501222
- Lidor Nili E Field Y Lubling Y Widom J Oren M Segal E p53 binds preferentially to genomic regions with high DNA-encoded nucleosome occupancy Genome research 2010 20 1361 1368 20716666 PMC2945185
- Lone IN Shukla MS Charles Richard JL Peshev ZY Dimitrov S Angelov D Binding of NF-kappaB to nucleosomes: effect of translational positioning, nucleosome remodeling and linker histone H1 PLoS genetics 2013 9 e1003830 24086160 PMC3784511
- Luger K Rechsteiner TJ Richmond TJ Preparation of nucleosome core particle from recombinant histones Methods Enzymol 1999 304 3 19 10372352
- Mavrich T Ioshikhes I Venters B Jiang C Tomsho L Qi J Schuster S Albert I Pugh B A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome Genome research 2008 18 1073 1083 18550805 PMC2493396
- Mullen AC Orlando DA Newman JJ Loven J Kumar RM Bilodeau S Reddy J Guenther MG DeKoter RP Young RA Master transcription factors determine cell-type-specific responses to TGF-beta signaling Cell 2011 147 565 576 22036565 PMC3212730
- Natoli G Maintaining cell identity through global control of genomic organization Immunity 2010 33 12 24 20643336
- Nelson H Finch J Luisi B Klug A The structure of an oligo(dA).oligo(dT) tract and its biological implications Nature 1987 330 221 226 3670410
- Ostuni R Piccolo V Barozzi I Polletti S Termanini A Bonifacio S Curina A Prosperini E Ghisletti S Natoli G Latent enhancers activated by stimulation in differentiated cells Cell 2013 152 157 171 23332752
- Pan Y Tsai C-J Ma B Nussinov R Mechanisms of transcription factor selectivity Trends in genetics: TIG 2010 26 75 83 20074831 PMC7316385
- Ramirez-Carrozzi VR Braas D Bhatt DM Cheng CS Hong C Doty KR Black JC Hoffmann A Carey M Smale ST A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling Cell 2009 138 114 128 19596239 PMC2712736
- Salmon-Divon M Dvinge H Tammoja K Bertone P PeakAnalyzer: genome-wide annotation of chromatin binding and modification loci BMC bioinformatics 2010 11 415 20691053 PMC2923140
- Scott EW Simon MC Anastasi J Singh H Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages Science 1994 265 1573 1577 8079170
- Segal E Fondufe-Mittendorf Y Chen L Thåström A Field Y Moore I Wang J-PZ Widom J A genomic code for nucleosome positioning Nature 2006 442 772 778 16862119 PMC2623244
- Stergachis AB Neph S Reynolds A Humbert R Miller B Paige SL Vernot B Cheng JB Thurman RE Sandstrom R Developmental fate and cellular maturity encoded in human regulatory DNA landscapes Cell 2013 154 888 903 23953118 PMC3962256
- Struhl K Segal E Determinants of nucleosome positioning Nature structural & molecular biology 2013 20 267 273 PMC3740156 23463311
- Suter B Schnappauf G Thoma F Poly(dA.dT) sequences exist as rigid DNA structures in nucleosome-free yeast promoters in vivo Nucleic acids research 2000 28 4083 4089 11058103 PMC113125
- Teif V Vainshtein Y Caudron-Herger MØ Mallm J-P Marth C Höfer T Rippe K Genome-wide nucleosome positioning during embryonic stem cell development Nature structural & molecular biology 2012 19 1185 1192 23085715
- Thurman RE Rynes E Humbert R Vierstra J Maurano MT Haugen E Sheffield NC Stergachis AB Wang H Vernot B The accessible chromatin landscape of the human genome Nature 2012 489 75 82 22955617 PMC3721348
- Tillo D Hughes T G+C content dominates intrinsic nucleosome occupancy BMC bioinformatics 2009 10 442 20028554 PMC2808325
- Tillo D Kaplan N Moore I Fondufe-Mittendorf Y Gossett A Field Y Lieb J Widom J Segal E Hughes T High nucleosome occupancy is encoded at human regulatory sequences PloS one 2010 5 PMC2817738 20161746
- Valouev A Johnson S Boyd S Smith C Fire A Sidow A Determinants of nucleosome organization in primary human cells Nature 2011 474 516 520 21602827 PMC3212987
- van der Heijden T van Vugt JJ Logie C van Noort J Sequence-based prediction of single nucleosome positioning and genome-wide nucleosome occupancy Proceedings of the National Academy of Sciences 2012 109 E2514 E2522 PMC3458375 22908247
- Visel A Blow MJ Li Z Zhang T Akiyama JA Holt A Plajzer-Frick I Shoukry M Wright C Chen F ChIP-seq accurately predicts tissue-specific activity of enhancers Nature 2009 457 854 858 19212405 PMC2745234
- Yang L Zhou T Dror I Mathelier A Wasserman WW Gordân R Rohs R TFBSshape: a motif database for DNA shape features of transcription factor binding sites Nucleic Acids Res 2014 42 D148 155 24214955 PMC3964943
- Zhang Y Liu T Meyer CA Eeckhoute J Johnson DS Bernstein BE Nussbaum C Myers RM Brown M Li W Model-based analysis of ChIP-Seq (MACS) Genome Biol 2008 9 R137 18798982 PMC2592715
- Zhang Z Wippo C Wal M Ward E Korber P Pugh B A packing mechanism for nucleosome organization reconstituted across a eukaryotic genome Science (New York, NY) 2011 332 977 980 PMC4852979 21596991
- Zhou T Yang L Lu Y Dror I Dantas Machado AC Ghane T Di Felice R Rohs R DNAshape: a method for the high-throughput prediction of DNA structural features on a genomic scale Nucleic acids research 2013 41 W56 62 23703209 PMC3692085
- Authors
- Barozzi, I., Simonatto, M., Bonifacio, S., Yang, L., Rohs, R., Ghisletti, S., & Natoli, G.
- Affiliations
- European Institute of Oncology (IT)
- University of Southern California (US)
- Corresponding author
- Natoli, Gioacchino
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 54
- Issue
- 5
- Pages
- 844-857
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4048654
- OpenAlex
- W1995841566
- Cited by
- 209
- References
- 61
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 15 · 2023: 12 · 2022: 18 · 2021: 11 · 2020: 15 · 2019: 19 · 2018: 20 · 2017: 22 · 2016: 25 · 2015: 23 · 2014: 8
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of General Medical Sciences (U01GM103804, R01GM106056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- transcription factor binding, nucleosome occupancy, enhancers, cis-regulatory elements, PU.1, nucleosome depletion, DNA sequence features, DNA shape, chromatin organization, transcriptional regulation
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Binding Sites, Cells, Cultured, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Models, Genetic, Nucleosomes, Proto-Oncogene Proteins, Trans-Activators, Consensus Sequence, Sequence Analysis, DNA, RNA, Small Interfering, Mice, Gene Knockdown Techniques, Support Vector Machine
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