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

Andrew Oldfield 1 Telmo Henriques 1, 2 Dhirendra Kumar 3, 1 Adam Burkholder 1 Senthilkumar Cinghu 1 Damien Paulet 4, 5 Brian Bennett 6 Pengyi Yang 1 Benjamin Scruggs 1 Christopher Lavender 1 Eric Rivals 5, 4 Karen Adelman 7, 2 Raja Jothi 1
1 ESCBL-NIEHS-NIH - Epigenetics and Stem Cell Biology Laboratory [Durham]
2 HMS - Harvard Medical School [Boston]
3 Maharishi Valmiki Hospital
4 MAB - Méthodes et Algorithmes pour la Bioinformatique
LIRMM - Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier
5 IBC - Institut de Biologie Computationnelle
6 Marquette University
7 NIEHS-NIH - National Institute of Environmental Health Sciences [Durham]
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.
Keywords : CCAAT-Binding Factor Promoter Regions Nucleosomes Mice Gene Knockdown Techniques Embryonic Stem Cells Metabolism Chromatin Transcription Initiation Site Small Interfering RNA Site Transcription Initiation
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Andrew Oldfield, Telmo Henriques, Dhirendra Kumar, Adam Burkholder, Senthilkumar Cinghu, et al.. NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.3072. ⟨10.1038/s41467-019-10905-7⟩. ⟨lirmm-02383488⟩

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