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Nat Commun. 2019 Jul 11;10(1):3072. doi: 10.1038/s41467-019-10905-7.

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

Author information

1
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA. andrew.oldfield@igh.cnrs.fr.
2
Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, 34396, France. andrew.oldfield@igh.cnrs.fr.
3
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
5
Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA.
6
Department of Computer Science, LIRMM, CNRS et Université de Montpellier, Montpellier, 34095, France.
7
Institut de Biologie Computationnelle (IBC), Université de Montpellier, Montpellier, 34095, France.
8
Charles Perkins Centre and School of Mathematics and Statistics, University of Sydney, Sydney, NSW 2006, Australia.
9
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA. karen_adelman@hms.harvard.edu.
10
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. karen_adelman@hms.harvard.edu.
11
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA. jothi@nih.gov.

Abstract

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.

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