L-Methionyl-L-Methionine dipeptide (Met-Met) functions more effectively than free Met in promoting mammary gland development and differentiation, but the underlying mechanisms remain largely unknown. This study was aimed to investigate the role and regulatory mechanisms of a novel mammary gland proliferation-associated long non-coding RNA (MGPNCR) in mammogenesis and lactogenesis during Met-Met supplementation. Nine-week-old ICR mice (n = 24, ~30 g) at pregnant day (PD) 0 were randomly divided into three groups. The control group was fed with the standard diet added with Met (8.2 g/kg) and received daily intraperitoneal (i.p.) injection of saline until PD17. The Met group was provided with the Met-devoid diet and daily i.p. injection of 35% Met (92-mmoL, based on 4.8 g/day dry matter intake) contained in the control diet, and the Met-Met group was provided with the Met-devoid diet and daily i.p. injection of 70-mmoL Met and 11-mmoL Met-Met which was equivalent to the same molar amount of Met in Met group. At PD17, mammary gland was collected for RNA sequencing analysis. A similar Met-deficiency model was also established using the mouse mammary epithelial cell HC11. Compared with the Met-Met group, MGPNCR was up-regulated in the Met group and was associated with suppressed cell viability and the expression of cyclin D and β-casein (<i>P</i> &lt; 0.05). Knockdown of MGPNCR promoted HC11 proliferation and milk protein synthesis, whereas ectopic MGPNCR expression suppressed mammary functions (<i>P</i> &lt; 0.05). We further clarified that up-regulated MGPNCR inhibited eukaryotic translation initiation factor 4B (eIF4B) phosphorylation at serine-422 by promoting its binding with the protein phosphatase 2A (PP2A). These results elucidated the regulatory mechanisms of dipeptide-mediated lncRNAs on cellular proliferation and milk protein synthesis, and further confirms the role of dipeptides in animal and human milk production.

Methionyl-methionine dipeptide improves mammogenesis and lactogenesis over free methionine by suppressing the expression of a novel long non-coding RNA MGPNCR that promotes dephosphorylation of eIF4B

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