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<p>Marbling (intramuscular fat) is a crucial determinant of beef palatability. Zinc finger protein 423 (ZNF423) plays a key role in adipocyte differentiation and lipid metabolism, but its regulatory mechanisms, particularly in bovine adipocytes, remain poorly understood. This study demonstrates that si-<i>ZNF423</i> inhibits adipocyte proliferation by disrupting the G1/S transition and down-regulating key proliferation markers. Additionally, <i>ZNF423</i> knockdown suppresses the expression of major adipogenic transcription factors (<i>PPARγ</i>, <i>C/EBPβ</i>) and lipid metabolism genes (<i>SCD1</i>, <i>FABP4</i>), resulting in reduced triglyceride (TG) accumulation and impaired lipid droplet formation. Transcriptomic and non-targeted metabolomic analyses indicated that <i>ZNF423</i> regulates adipogenesis through pathways involving retinoic acid (RA) signaling. ChIP and dual luciferase assays confirmed that <i>ZNF423</i> directly binds to the promoters of <i>SLC45A2</i> and <i>SNCG</i>, identifying these genes as novel downstream targets. Notably, RA treatment compensates for the effects of si-<i>ZNF423</i> knockdown, not only restoring and significantly enhancing <i>ZNF423</i> activity and downstream adipogenic processes, highlighting a conserved interplay between <i>ZNF423</i> and RA signaling in bovine adipogenesis. This study provides new insights into the molecular mechanisms of bovine fat development, offering potential targets for improving beef quality.</p> Graphical abstract <p>Graphical abstract proposed model for RA- and ZNF423-mediated regulation of bovine adipogenesis. RA enters bovine adipocytes via passive diffusion and binds to intracellular carrier proteins, such as CRABP-II, which deliver RA to the RAR and RXR. In the absence of RA, RAR and RXR are bound to heat shock proteins (HSPs) in an inactive state. Upon RA binding, RAR and RXR form a heterodimer, which translocates into the nucleus and binds to retinoic acid response elements (RAREs) on target gene promoters, including ZNF423. ZNF423 subsequently regulates adipogenesis by directly binding to the promoter of target genes such as SLC45A2 and SNCG, leading to the activation of downstream signaling pathways such as PI3K-AKT and ERK, respectively. These pathways influence the expression of adipocyte-specific transcription factors, including PPARγ, C/EBP, and SREBP, which regulate lipid metabolism and adipocyte differentiation. Additionally, ZNF423 indirectly modulates glycolytic enzyme activity and glucose transporter (GLUT) expression, impacting intracellular ATP levels and pyruvate metabolism, essential for lipid synthesis. This model highlights the central role of RA, ZNF423, and their downstream targets in orchestrating bovine adipogenesis and metabolic regulation</p>

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Multi-Omics analysis unveils the regulatory mechanism of ZNF423 in bovine intramuscular fat formation

  • 期刊论文

  • 发表日期：

    2025年10月13日

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  • Xiaoyu Song,
  • Jiupan Zhang,
  • Yaping Song,
  • Sayed Haidar Abbas Raza,
  • Sameer Dinkar Pant,
  • Linsen Zan,
  • Guijie Zhang,
  • Dawei Wei

摘要

Marbling (intramuscular fat) is a crucial determinant of beef palatability. Zinc finger protein 423 (ZNF423) plays a key role in adipocyte differentiation and lipid metabolism, but its regulatory mechanisms, particularly in bovine adipocytes, remain poorly understood. This study demonstrates that si-ZNF423 inhibits adipocyte proliferation by disrupting the G1/S transition and down-regulating key proliferation markers. Additionally, ZNF423 knockdown suppresses the expression of major adipogenic transcription factors (PPARγ, C/EBPβ) and lipid metabolism genes (SCD1, FABP4), resulting in reduced triglyceride (TG) accumulation and impaired lipid droplet formation. Transcriptomic and non-targeted metabolomic analyses indicated that ZNF423 regulates adipogenesis through pathways involving retinoic acid (RA) signaling. ChIP and dual luciferase assays confirmed that ZNF423 directly binds to the promoters of SLC45A2 and SNCG, identifying these genes as novel downstream targets. Notably, RA treatment compensates for the effects of si-ZNF423 knockdown, not only restoring and significantly enhancing ZNF423 activity and downstream adipogenic processes, highlighting a conserved interplay between ZNF423 and RA signaling in bovine adipogenesis. This study provides new insights into the molecular mechanisms of bovine fat development, offering potential targets for improving beef quality.

Graphical abstract

Graphical abstract proposed model for RA- and ZNF423-mediated regulation of bovine adipogenesis. RA enters bovine adipocytes via passive diffusion and binds to intracellular carrier proteins, such as CRABP-II, which deliver RA to the RAR and RXR. In the absence of RA, RAR and RXR are bound to heat shock proteins (HSPs) in an inactive state. Upon RA binding, RAR and RXR form a heterodimer, which translocates into the nucleus and binds to retinoic acid response elements (RAREs) on target gene promoters, including ZNF423. ZNF423 subsequently regulates adipogenesis by directly binding to the promoter of target genes such as SLC45A2 and SNCG, leading to the activation of downstream signaling pathways such as PI3K-AKT and ERK, respectively. These pathways influence the expression of adipocyte-specific transcription factors, including PPARγ, C/EBP, and SREBP, which regulate lipid metabolism and adipocyte differentiation. Additionally, ZNF423 indirectly modulates glycolytic enzyme activity and glucose transporter (GLUT) expression, impacting intracellular ATP levels and pyruvate metabolism, essential for lipid synthesis. This model highlights the central role of RA, ZNF423, and their downstream targets in orchestrating bovine adipogenesis and metabolic regulation