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<p>Essential amino acids (EAA) may alter bovine mammary epithelial cell (BMEC) activities through regulation of gene transcription. For this study, we used pathway analysis of RNA-sequencing data to identify upstream transcription factors (TF) that potentially mediate the effects of single EAA deficiency on BMEC. Differentiated BMEC were cultured in 1 of 4 treatment media representing normal physiological concentrations of all amino acids (CTL), or ¼ the normal concentration of histidine (LH), lysine (LK), or methionine (LM). After 48&#xa0;h, rates of DNA synthesis were reduced 30 to 40% by each of the deficiencies. Protein synthesis rate was 30 to 50% lower in LK and LM but was unaffected by LH. Up-regulated upstream TF included those related to nutrient stress, interferon signaling, and suppression of cell population growth. Down-regulated TF were primarily related to cell cycle progression. An array of classic ATF4 targets increased in response to EAA deficiencies including amino acid transporters, branched-chain aminotransferase, aminoacyl-tRNA synthetases, sestrin2 (a leucine sensor), and activators of apoptosis. Interferon signaling emerged as a novel pathway activated by EAA deficiencies, possibly contributing to reduced cell proliferation and protein synthesis. In contrast, the MAPK signaling pathway was unaffected. Expression of hypoxia-inducible factor 1α (HIF1A) increased, consistent with an anti-proliferative role. Downregulation of Forkhead box protein M1 (FOXM1) likely contributed to slower cell proliferation. These findings reveal a complex network of transcriptional regulators and signaling pathways influenced by EAA availability and shed light on the nutritional regulation of milk protein production by dairy cows.</p>

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An RNA-sequencing analysis to determine potential upstream transcriptional regulators of essential amino acid deficiency responses in bovine mammary epithelial cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Boning Li,
  • Dave J. Innes,
  • Eduardo S. Ribeiro,
  • John Doelman,
  • Sergio A. Burgos,
  • John P. Cant

摘要

Essential amino acids (EAA) may alter bovine mammary epithelial cell (BMEC) activities through regulation of gene transcription. For this study, we used pathway analysis of RNA-sequencing data to identify upstream transcription factors (TF) that potentially mediate the effects of single EAA deficiency on BMEC. Differentiated BMEC were cultured in 1 of 4 treatment media representing normal physiological concentrations of all amino acids (CTL), or ¼ the normal concentration of histidine (LH), lysine (LK), or methionine (LM). After 48 h, rates of DNA synthesis were reduced 30 to 40% by each of the deficiencies. Protein synthesis rate was 30 to 50% lower in LK and LM but was unaffected by LH. Up-regulated upstream TF included those related to nutrient stress, interferon signaling, and suppression of cell population growth. Down-regulated TF were primarily related to cell cycle progression. An array of classic ATF4 targets increased in response to EAA deficiencies including amino acid transporters, branched-chain aminotransferase, aminoacyl-tRNA synthetases, sestrin2 (a leucine sensor), and activators of apoptosis. Interferon signaling emerged as a novel pathway activated by EAA deficiencies, possibly contributing to reduced cell proliferation and protein synthesis. In contrast, the MAPK signaling pathway was unaffected. Expression of hypoxia-inducible factor 1α (HIF1A) increased, consistent with an anti-proliferative role. Downregulation of Forkhead box protein M1 (FOXM1) likely contributed to slower cell proliferation. These findings reveal a complex network of transcriptional regulators and signaling pathways influenced by EAA availability and shed light on the nutritional regulation of milk protein production by dairy cows.