Gene expression is globally regulated by interacting nucleobase supply and mRNA composition demand: a mechanism disrupted by multiple disease states and drug treatments
-д хадгалсан:
| -д хэвлэсэн: | bioRxiv (Dec 23, 2024) |
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| Үндсэн зохиолч: | |
| Хэвлэсэн: |
Cold Spring Harbor Laboratory Press
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| Нөхцлүүд: | |
| Онлайн хандалт: | Citation/Abstract Full Text - PDF Full text outside of ProQuest |
| Шошгууд: |
Шошго байхгүй, Энэхүү баримтыг шошголох эхний хүн болох!
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MARC
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| 001 | 3148678922 | ||
| 003 | UK-CbPIL | ||
| 022 | |a 2692-8205 | ||
| 024 | 7 | |a 10.1101/2024.12.23.630131 |2 doi | |
| 035 | |a 3148678922 | ||
| 045 | 0 | |b d20241223 | |
| 100 | 1 | |a Benjamin Simon Pickard | |
| 245 | 1 | |a Gene expression is globally regulated by interacting nucleobase supply and mRNA composition demand: a mechanism disrupted by multiple disease states and drug treatments | |
| 260 | |b Cold Spring Harbor Laboratory Press |c Dec 23, 2024 | ||
| 513 | |a Working Paper | ||
| 520 | 3 | |a Conventional expression studies quantify messenger RNA (mRNA) transcript levels gene-by-gene. We recently showed that protein expression is modulated at a global scale by amino acid availability, suggesting that mRNA expression levels might be similarly affected by nucleobase supply. Re-analysis of transcriptomic datasets confirmed that nucleobase supply and mRNA A+U:C+G sequence composition interact to shape a global profile of expression which can be represented by simple numerical outputs. In mammals, each separate organ and cell-type displays a distinct baseline profile of expression, influenced by differentiation state. Expression profiles shift dynamically across the circadian day and the menstrual cycle. They are also significantly distorted by viral infection, multiple complex genetic disorders (including Alzheimer's disease, schizophrenia, and autoimmune disorders), and after treatment with 115 of the 597 chemical entities analysed. These entities included known toxins, but also many commonly prescribed medications such as antibiotics and proton pump inhibitors, thus revealing a new mechanism of drug action and side-effect. A role for nucleobase supply is supported by the actions of nucleobase analogue treatments and by a model of the nucleobase metabolism disorder, Lesch-Nyhan syndrome. On the demand-side, mRNAs at compositional extremes are over-represented in key gene ontologies including transcription and cell division, making these processes particularly sensitive to swings in global expression. This permits efficient en bloc reprogramming of cell state through simple changes in nucleobase proportion and supply. It is also proposed that this mechanism helped mitigate the loss of essential amino acid synthesis in higher organisms. In summary, global expression regulation is invisible to conventional transcriptomic analysis, but its measurement allows a useful distinction between active, promoter-mediated gene expression changes and passive, cell state-dependent transcriptional competence. Linking metabolism directly to expression offers an entirely new perspective on evolution, disease aetiopathology (including GxE interactions), and the nature of the pharmacological response.Competing Interest StatementThe authors have declared no competing interest. | |
| 653 | |a Proton pump inhibitors | ||
| 653 | |a Gene expression | ||
| 653 | |a Cell division | ||
| 653 | |a Amino acid composition | ||
| 653 | |a Amino acid sequence | ||
| 653 | |a Lesch-Nyhan syndrome | ||
| 653 | |a Genetic disorders | ||
| 653 | |a Drug metabolism | ||
| 653 | |a Cell differentiation | ||
| 653 | |a Metabolism | ||
| 653 | |a Transcriptomics | ||
| 653 | |a Schizophrenia | ||
| 653 | |a Neurodegenerative diseases | ||
| 653 | |a Nucleotide sequence | ||
| 653 | |a Circadian rhythms | ||
| 653 | |a Autoimmune diseases | ||
| 653 | |a Alzheimer's disease | ||
| 653 | |a Mental disorders | ||
| 653 | |a Menstrual cycle | ||
| 653 | |a Antibiotics | ||
| 773 | 0 | |t bioRxiv |g (Dec 23, 2024) | |
| 786 | 0 | |d ProQuest |t Biological Science Database | |
| 856 | 4 | 1 | |3 Citation/Abstract |u https://www.proquest.com/docview/3148678922/abstract/embedded/L8HZQI7Z43R0LA5T?source=fedsrch |
| 856 | 4 | 0 | |3 Full Text - PDF |u https://www.proquest.com/docview/3148678922/fulltextPDF/embedded/L8HZQI7Z43R0LA5T?source=fedsrch |
| 856 | 4 | 0 | |3 Full text outside of ProQuest |u https://www.biorxiv.org/content/10.1101/2024.12.23.630131v1 |