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

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. 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 demonstrate that NF-Y is a central player in TSS selection in metazoans and highlight the deleterious consequences of inaccurate transcription initiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE115110 | GEO | 2019/07/01

REPOSITORIES: GEO

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Project description:Unlike all other bacteria, the physiology of cyanobacteria is based on the assimilation of organic matter from inorganic carbon driven by oxygenic photosynthesis. This setting poses special regulatory challenges, particularly in integrating carbon and nitrogen metabolism. Several regulatory factors control the primary nitrogen metabolism, such as the PII protein and proteins interacting with it (PirA, PirC or PipX), or the inactivating factors IF7 and IF17 impacting glutamine synthetase activity. However, regulatory proteins of other enzymes in the nitrogen assimilation pathway have not been described thus far. Here, we show that the 81 amino acids regulatory protein NirP1 in the cyanobacterium Synechocystis sp. PCC 6803 functions as an inhibitor of nitrite reductase, a central enzyme in the assimilation of ammonia from nitrate/nitrite. Ectopic overexpression of the nirP1 gene under standard growth conditions led to a pigmentation phenotype and delayed growth, which was correlated by the excretion of nitrite and dramatic changes in metabolite pools. We show that nitrite excretion occurs in Synechocystis wild type cells upon the shift from high CO2 (HC) to low CO2 (LC) conditions when NirP1 expression becomes activated. The expression of nirP1 is controlled by two transcription factors, NtcA, which binds to a recognition site in a repressive position above the transcription start site (TSS), and an activator, which probably binds to an element 60 to 43 nt upstream of the TSS. Therefore, the joint activity of NtcA and this activator leads to the observed induction of NirP1 under LC conditions, whereas it is repressed by shifts to nitrogen starvation. The data demonstrate that NirP1 plays a crucial role in the coordination of C and N primary metabolism in cyanobacteria by targeting the activity of one of the central enzymes. In natural environments, the excreted nitrite will be utilized by other microorganisms; therefore, NirP1 will ultimately impact the activities and composition of the surrounding microbiome.

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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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