Skip to main content Accessibility help
×
Home
Hostname: page-component-7f7b94f6bd-2h7tr Total loading time: 0.3 Render date: 2022-06-28T21:45:29.268Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Isoleucine stimulates mTOR and SREBP-1c gene expression for milk synthesis in mammary epithelial cells through BRG1-mediated chromatin remodelling

Published online by Cambridge University Press:  20 May 2022

Qi Hao
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China
Zhe Wang
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China College of Life Science, Northeast Agricultural University, Harbin150030, People’s Republic of China
Lulu Wang
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China
Meihong Han
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China
Minghui Zhang
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China College of Life Science, Northeast Agricultural University, Harbin150030, People’s Republic of China
Xuejun Gao*
Affiliation:
College of Animal Science, Yangtze University, Jingzhou434023, People’s Republic of China
*
*Corresponding author: Xuejun Gao, email gaoxj53901@163.com

Abstract

Several amino acids can stimulate milk synthesis in mammary epithelial cells (MEC); however, the regulatory role of isoleucine (Ile) and underlying molecular mechanism remain poorly understood. In this study, we aimed to evaluate the regulatory effects of Ile on milk protein and fat synthesis in MEC and reveal the mediation mechanism of Brahma-related gene 1 (BRG1) on this regulation. Ile dose dependently affected milk protein and fat synthesis, mechanistic target of rapamycin (mTOR) phosphorylation, sterol regulatory element binding protein 1c (SREBP-1c) expression and maturation, and BRG1 protein expression in bovine MEC. Phosphatidylinositol 3 kinase (PI3K) inhibition by LY294002 treatment blocked the stimulation of Ile on BRG1 expression. BRG1 knockdown and gene activation experiments showed that it mediated the stimulation of Ile on milk protein and fat synthesis, mTOR phosphorylation, and SREBP-1c expression and maturation in MEC. ChIP-PCR analysis detected that BRG1 bound to the promoters of mTOR and SREBP-1c, and ChIP-qPCR further detected that these bindings were increased by Ile stimulation. In addition, BRG1 positively regulated the binding of H3K27ac to these two promoters, while it negatively affected the binding of H3K27me3 to these promoters. BRG1 knockdown blocked the stimulation of Ile on these two gene expressions. The expression of BRG1 was higher in mouse mammary gland in the lactating period, compared with that in the puberty or dry period. Taken together, these experimental data reveal that Ile stimulates milk protein and fat synthesis in MEC via the PI3K-BRG1-mTOR/SREBP-1c pathway.

Type
Research Article
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of The Nutrition Society

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

These authors contributed equally to this work.

References

Dias, K, Garcia, S, Islam, MR, et al. (2019) Milk yield, milk composition, and the nutritive value of feed accessed varies with milking order for pasture-based dairy cattle. Animal 9, 60.CrossRefGoogle ScholarPubMed
Lucey, JA, Otter, D & Horne, DS (2017) A 100-year review: progress on the chemistry of milk and its components. J Dairy Sci 100, 99169932.CrossRefGoogle ScholarPubMed
Roy, D, Ye, A, Moughan, PJ, et al. (2020) Composition, structure, and digestive dynamics of milk from different species – a review. Front Nutr 7, 577759.CrossRefGoogle ScholarPubMed
Osorio, JS, Lohakare, J & Bionaz, M (2016) Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation. Physiol Genomics 48, 231256.CrossRefGoogle ScholarPubMed
Li, YW, Cao, Y, Wang, JX, et al. (2020) Kp-10 promotes bovine mammary epithelial cell proliferation by activating GPR54 and its downstream signaling pathways. J Cell Physiol 235, 44814493.CrossRefGoogle ScholarPubMed
Dong, X, Zhou, Z, Saremi, B, et al. (2018) Varying the ratio of Lys:Met while maintaining the ratios of Thr:Phe, Lys:Thr, Lys:His, and Lys:Val alters mammary cellular metabolites, mammalian target of rapamycin signaling, and gene transcription. J Dairy Sci 101, 17081718.CrossRefGoogle ScholarPubMed
Li, N, Zhao, F, Wei, CJ, et al. (2014) Function of SREBP1 in the milk fat synthesis of dairy cow mammary epithelial cells. Int J Mol Sci 15, 1699817013.CrossRefGoogle ScholarPubMed
Fan, XY, Qiu, LH, Teng, XH, et al. (2020) Effect of INSIG1 on the milk fat synthesis of buffalo mammary epithelial cells. J Dairy Res 87, 349355.CrossRefGoogle ScholarPubMed
Qiu, YW, Qu, B, Zhen, Z, et al. (2019) Leucine promotes milk synthesis in bovine mammary epithelial cells via the PI3K-DDX59 signaling. J Agr Food Chem 67, 88848895.CrossRefGoogle ScholarPubMed
Xiao, J, Xiong, YN, Yang, LT, et al. (2021) POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation. Protein Cell 12, 279296.CrossRefGoogle ScholarPubMed
Zhang, Y, Li, C, Hu, C, et al. (2019) Lin28 enhances de novo fatty acid synthesis to promote cancer progression via SREBP-1. EMBO Rep 20, e48115.CrossRefGoogle ScholarPubMed
Son, SM, Park, SJ, Lee, H, et al. (2019) Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab 29, 192201.e7.CrossRefGoogle ScholarPubMed
Nie, C, He, T, Zhang, W, et al. (2018) Branched chain amino acids: beyond nutrition metabolism. Int J Mol Sci 19, 954.CrossRefGoogle ScholarPubMed
Li, X, Li, P, Wang, L, et al. (2019) Lysine enhances the stimulation of fatty acids on milk fat synthesis via the GPRC6A-PI3K-FABP5 signaling in bovine mammary epithelial cells. J Agric Food Chem 67, 70057015.CrossRefGoogle ScholarPubMed
Li, P, Zhou, C, Li, X, et al. (2019) CRTC2 is a key mediator of amino acid-induced milk fat synthesis in mammary epithelial cells. J Agric Food Chem 67, 1051310520.CrossRefGoogle ScholarPubMed
Che, L, Xu, M, Gao, K, et al. (2019) Valine increases milk fat synthesis in mammary gland of gilts through stimulating AKT/MTOR/SREBP1 pathway. Biol Reprod 101, 126137.CrossRefGoogle Scholar
Guo, L, Liang, ZQ, Zheng, C, et al. (2018) Leucine affects -amylase synthesis through PI3K/Akt-mTOR signaling pathways in pancreatic acinar cells of dairy calves. J Agric Food Chem 66, 51495156.CrossRefGoogle ScholarPubMed
Huo, N, Yu, M, Li, X, et al. (2019) PURB is a positive regulator of amino acid-induced milk synthesis in bovine mammary epithelial cells. J Cell Physiol 234, 69927003.CrossRefGoogle ScholarPubMed
Huang, X, Zang, Y, Zhang, M, et al. (2017) Nuclear factor of kappaB1 is a key regulator for the transcriptional activation of milk synthesis in bovine mammary epithelial cells. DNA Cell Biol 36, 295302.CrossRefGoogle ScholarPubMed
Luo, C, Qi, H, Huang, X, et al. (2019) GlyRS is a new mediator of amino acid-induced milk synthesis in bovine mammary epithelial cells. J Cell Physiol 234, 29732983.CrossRefGoogle ScholarPubMed
Mashtalir, N, D’Avino, AR, Michel, BC, et al. (2018) Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 12721288.e20.CrossRefGoogle ScholarPubMed
Wu, Q, Lian, JB, Stein, JL, et al. (2017) The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics 9, 919931.CrossRefGoogle ScholarPubMed
Wu, T, Kamikawa, YF & Donohoe, ME (2018) Brd4's bromodomains mediate histone H3 acetylation and chromatin remodeling in pluripotent cells through P300 and Brg1. Cell Rep 25, 17561771.CrossRefGoogle ScholarPubMed
Marino, MM, Rega, C, Russo, R, et al. (2019) Interactome mapping defines BRG1, a component of the SWI/SNF chromatin remodeling complex, as a new partner of the transcriptional regulator CTCF. J Biol Chem 294, 861873.CrossRefGoogle ScholarPubMed
Zhu, X, Lan, B, Yi, X, et al. (2020) HRP2-DPF3a–BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription. Nucleic Acids Res 48, 65636582.CrossRefGoogle ScholarPubMed
Hartley, A, Leung, HY & Ahmad, I (2021) Targeting the BAF complex in advanced prostate cancer. Expert Opin Drug Discov 16, 173181.CrossRefGoogle ScholarPubMed
Wang, Y, Yang, CH, Schultz, AP, et al. (2021) Brahma-Related Gene-1 (BRG1) promotes the malignant phenotype of glioblastoma cells. J Cell Mol Med 25, 29562966.CrossRefGoogle ScholarPubMed
Wang, P, Song, X, Cao, D, et al. (2020) Oncogene-dependent function of BRG1 in hepatocarcinogenesis. Cell Death Dis 11, 91.CrossRefGoogle ScholarPubMed
Qi, H, Wang, L, Zhang, M, et al. (2022) Methionine and leucine induce ARID1A degradation to promote mTOR expression and milk synthesis in mammary epithelial cells. J Nutr Biochem 101, 108924.CrossRefGoogle ScholarPubMed
Qi, H, Meng, C, Jin, X, et al. (2018) Methionine promotes milk protein and fat synthesis and cell proliferation via the SNAT2-PI3K signaling pathway in bovine mammary epithelial cells. J Agric Food Chem 66, 1102711033.CrossRefGoogle ScholarPubMed
Sobczak, M, Pietrzak, J, Płoszaj, T, et al. (2020) BRG1 activates proliferation and transcription of cell cycle-dependent genes in breast cancer cells. Cancers 12, 349.CrossRefGoogle ScholarPubMed
Sun, L, Yuan, Y, Chen, J, et al. (2019) Brahma related gene 1 (BRG1) regulates breast cancer cell migration and invasion by activating MUC1 transcription. Biochem Biophys Res Commun 511, 536543.CrossRefGoogle ScholarPubMed
Li, N, Li, M, Hong, W, et al. (2018) Brg1 regulates pro-lipogenic transcription by modulating SREBP activity in hepatocytes. Biochim Biophys Acta Mol Basis Dis 1864, 28812889.CrossRefGoogle ScholarPubMed
Kong, M, Zhu, Y, Shao, J, et al. (2021) The chromatin remodeling protein BRG1 regulates SREBP maturation by activating SCAP transcription in hepatocytes. Front Cell Dev Biol 9, 622866.CrossRefGoogle ScholarPubMed
Wolfson, RL & Sabatini, DM (2017) The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab 26, 301309.CrossRefGoogle ScholarPubMed
Takahara, T, Amemiya, Y, Sugiyama, R, et al. (2020) Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. J Biomed Sci 27, 87.CrossRefGoogle ScholarPubMed
Condon, KJ & Sabatini, DM (2019) Nutrient regulation of mTORC1 at a glance. J Cell Sci 132, jcs222570.CrossRefGoogle ScholarPubMed
Huang, LY, Zhao, J, Chen, H, et al. (2018) SCF (FBW7)-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nat Commun 9, 3569.CrossRefGoogle ScholarPubMed
Jung, I, Sohn, DH, Choi, J, et al. (2012) SRG3/mBAF155 stabilizes the SWI/SNF–like BAF complex by blocking CHFR mediated ubiquitination and degradation of its major components. Biochem Biophys Res Commun 418, 512517.CrossRefGoogle ScholarPubMed
Wang, SA, Young, MJ, Jeng, WY, et al. (2020) USP24 stabilizes bromodomain containing proteins to promote lung cancer malignancy. Sci Rep 10, 20870.CrossRefGoogle ScholarPubMed
Luo, Q, Wu, X, Nan, Y, et al. (2020) TRIM32/USP11 balances ARID1A stability and the oncogenic/tumor-suppressive status of squamous cell carcinoma. Cell Rep 30, 98111.e5.CrossRefGoogle ScholarPubMed
Igolkina, AA, Zinkevich, A, Karandasheva, KO, et al. (2019) H3K4me3, H3K9ac, H3K27ac, H3K27me3 and H3K9me3 histonetags suggest distinct regulatory evolution of open and condensed chromatin landmarks. Cells 8, 1034.CrossRefGoogle ScholarPubMed
Li, Y, Li, H & Zhou, L (2020) EZH2-mediated H3K27me3 inhibits ACE2 expression. Biochem Biophys Res Commun 526, 947952.CrossRefGoogle ScholarPubMed
Bandara, TAMK, Otsuka, K, Matsubara, S, et al. (2021) A dual enhancer-silencer element, DES-K16, in mouse spermatocyte-derived GC-2spd(ts) cells. Biochem Biophys Res Commun 534, 10071012.CrossRefGoogle ScholarPubMed
He, S, Wu, Z, Tian, Y, et al. (2020) Structure of nucleosome–bound human BAF complex. Sci 367, 875881.CrossRefGoogle ScholarPubMed
Abou, EI, Hassan, M, Yu, T, et al. (2015) Polycomb repressive complex2 confers BRG1 dependency on the CIITA locus. J Immunol 194, 50075013.CrossRefGoogle Scholar
Trotter, KW & Archer, TK (2008) The BRG1 transcriptional coregulator. Nucl Recept Signal 6, e004.CrossRefGoogle ScholarPubMed
Ji, Y, Wu, Z, Dai, Z, et al. (2017) Fetal and neonatal programming of postnatal growth and feed efficiency in swine. J Anim Sci Biotechnol 8, 42.CrossRefGoogle ScholarPubMed
Marín-García, PJ & Llobat, L (2021) How does protein nutrition affect the epigenetic changes in pig? A review. Animal 11, 544.CrossRefGoogle ScholarPubMed
Supplementary material: File

Hao et al. supplementary material

Figures S1-S5
Download Hao et al. supplementary material(File)
File 3 MB

Save article to Kindle

To save this article to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Isoleucine stimulates mTOR and SREBP-1c gene expression for milk synthesis in mammary epithelial cells through BRG1-mediated chromatin remodelling
Available formats
×

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Isoleucine stimulates mTOR and SREBP-1c gene expression for milk synthesis in mammary epithelial cells through BRG1-mediated chromatin remodelling
Available formats
×

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Isoleucine stimulates mTOR and SREBP-1c gene expression for milk synthesis in mammary epithelial cells through BRG1-mediated chromatin remodelling
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *