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      NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region


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          Faithful transcription initiation is critical for accurate gene expression, yet the mechanisms underlying specific transcription start site (TSS) selection in mammals remain unclear. Here, we show that the histone-fold domain protein NF-Y, a ubiquitously expressed transcription factor, controls the fidelity of transcription initiation at gene promoters in mouse embryonic stem cells. We report that NF-Y maintains the region upstream of TSSs in a nucleosome-depleted state while simultaneously protecting this accessible region against aberrant and/or ectopic transcription initiation. We find that loss of NF-Y binding in mammalian cells disrupts the promoter chromatin landscape, leading to nucleosomal encroachment over the canonical TSS. Importantly, this chromatin rearrangement is accompanied by upstream relocation of the transcription pre-initiation complex and ectopic transcription initiation. Further, this phenomenon generates aberrant extended transcripts that undergo translation, disrupting gene expression profiles. These results suggest NF-Y is a central player in TSS selection in metazoans and highlight the deleterious consequences of inaccurate transcription initiation.


          The mechanisms underlying specific TSS selection in mammals remain unclear. Here the authors show that the ubiquitously expressed transcription factor NF-Y regulate fidelity of transcription initiation at gene promoters, maintaining the region upstream of TSSs in a nucleosome-depleted state, while protecting this region from ectopic transcription initiation.

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          Genome-wide analysis of mammalian promoter architecture and evolution.

          Mammalian promoters can be separated into two classes, conserved TATA box-enriched promoters, which initiate at a well-defined site, and more plastic, broad and evolvable CpG-rich promoters. We have sequenced tags corresponding to several hundred thousand transcription start sites (TSSs) in the mouse and human genomes, allowing precise analysis of the sequence architecture and evolution of distinct promoter classes. Different tissues and families of genes differentially use distinct types of promoters. Our tagging methods allow quantitative analysis of promoter usage in different tissues and show that differentially regulated alternative TSSs are a common feature in protein-coding genes and commonly generate alternative N termini. Among the TSSs, we identified new start sites associated with the majority of exons and with 3' UTRs. These data permit genome-scale identification of tissue-specific promoters and analysis of the cis-acting elements associated with them.
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            A genomic code for nucleosome positioning.

            Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome-DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain approximately 50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.
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              The DNA-encoded nucleosome organization of a eukaryotic genome.

              Nucleosome organization is critical for gene regulation. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers, competition with site-specific DNA-binding proteins, and the DNA sequence preferences of the nucleosomes themselves. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for approximately 40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.

                Author and article information

                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                11 July 2019
                11 July 2019
                : 10
                : 3072
                [1 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Epigenetics and Stem Cell Biology Laboratory, , National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, ; Durham, NC 27709 USA
                [2 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Biological Chemistry and Molecular Pharmacology, , Harvard Medical School, ; Boston, MA 02115 USA
                [3 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Integrative Bioinformatics Support Group, , National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, ; Durham, NC 27709 USA
                [4 ]ISNI 0000 0004 0599 0488, GRID grid.464638.b, Department of Computer Science, , LIRMM, CNRS et Université de Montpellier, ; Montpellier, 34095 France
                [5 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Institut de Biologie Computationnelle (IBC), , Université de Montpellier, ; Montpellier, 34095 France
                [6 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Present Address: Institute of Human Genetics, CNRS, , University of Montpellier, ; Montpellier, 34396 France
                [7 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Present Address: Charles Perkins Centre and School of Mathematics and Statistics, , University of Sydney, ; Sydney, NSW 2006 Australia
                Author information
                © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                : 21 December 2018
                : 27 May 2019
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: 1ZIAES101987
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                © The Author(s) 2019

                nucleosomes, transcription


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