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BMC Medicine
Published in: BMC Medicine 1/2022

01-12-2022 | Research article

Role of EZH2-mediated H3K27me3 in placental ADAM12-S expression: implications for fetoplacental growth

Authors: Ya-nan Zhu, Xiao-wen Gan, Fan Pan, Xiao-tian Ni, Leslie Myatt, Wang-sheng Wang, Kang Sun

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Enhancer of zeste homolog 2 (EZH2)-mediated histone 3 lysine 27 trimethylation (H3K27me3) is a transcription silencing mark, which is indispensable for cell lineage specification at the early blastocyst stage. This epigenetic repression is maintained in placental cytotrophoblasts but is lifted when cytotrophoblasts differentiate into syncytiotrophoblasts. However, the physiological impact of this lift remains elusive. Here, we investigated whether lifting EZH2-mediated H3K27me3 during syncytialization upregulates the expression of a short secretory isoform of a disintegrin and metalloprotease 12 (ADAM12-S), a well-recognized placenta-derived protease that cleaves insulin-like growth factor binding protein 3 to increase insulin-like growth factor (IGF) bioavailability for the stimulation of fetoplacental growth. The transcription factor and the upstream signal involved were also explored.

Methods

Human placenta tissue and cultured primary human placental cytotrophoblasts were utilized to investigate the role of EZH2-mediated H3K27me3 in ADAM12-S expression and the associated transcription factor and upstream signal during syncytialization. A mouse model was used to examine whether inhibition of EZH2-mediated H3K27me3 regulates placental ADAM12-S expression and fetoplacental growth.

Results

EZH2 and ADAM12 are distributed primarily in villous cytotrophoblasts and syncytiotrophoblasts, respectively. Increased ADAM12-S expression, decreased EZH2 expression, and decreased EZH2/H3K27me3 enrichment at the ADAM12 promoter were observed during syncytialization. Knock-down of EZH2 further increased ADAM12-S expression in trophoblasts. Syncytialization was also accompanied by increased STAT5B expression and phosphorylation as well as its enrichment at the ADAM12 promoter. Knock-down of STAT5B attenuated ADAM12-S expression during syncytialization. Epidermal growth factor (EGF) was capable of inducing ADAM12-S expression via stimulation of STAT5B expression and phosphorylation during syncytialization. Mouse studies revealed that administration of an EZH2 inhibitor significantly increased ADAM12-S levels in maternal blood and fetoplacental weights along with decreased H3K27me3 abundance and increased ADAM12-S expression in the placenta.

Conclusions

Lifting EZH2-mediated H3K27me3 increases ADAM12-S expression during syncytialization with the participation of EGF-activated STAT5B, which may lead to elevation of ADAM12-S level in maternal blood resulting in increased IGF bioavailability for the stimulation of fetoplacental growth in pregnancy. Our studies suggest that the role of EZH2-mediated H3K27me3 may switch from cell lineage specification at the early blastocyst stage to regulation of fetoplacental growth in later gestation.
Literature
1.
2.
O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol. 2001;21(13):4330–6.PubMedPubMedCentralCrossRef
3.
Paro R, Strutt H, Cavalli G. Heritable chromatin states induced by the polycomb and trithorax group genes. Novartis Found Symp. 1998;214:51–61 (discussion 61-56, 104-113).PubMed
4.
Zuo R, Liu X, Wang W, Li W, Ying H, Sun K. A repressive role of enhancer of zeste homolog 2 in 11beta-hydroxysteroid dehydrogenase type 2 expression in the human placenta. J Biol Chem. 2017;292(18):7578–87.PubMedPubMedCentralCrossRef
5.
Zhu P, Wang W, Zuo R, Sun K. Mechanisms for establishment of the placental glucocorticoid barrier, a guard for life. Cell Mol Life Sci. 2019;76(1):13–26.PubMedCrossRef
6.
Forbes K, Westwood M. The IGF axis and placental function a mini review. Horm Res. 2008;69(3):129–37.PubMed
7.
Hiden U, Glitzner E, Hartmann M, Desoye G. Insulin and the IGF system in the human placenta of normal and diabetic pregnancies. J Anat. 2009;215(1):60–8.PubMedPubMedCentralCrossRef
8.
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12(3):159–69.PubMedCrossRef
9.
Blaydes JE, Berry J. A comparative evaluation of 9–0 monofilament and 9–0 braid polyglactin 910 in cataract surgery (intracapsular, extracapsular, and phacoemulsification). Ophthalmic Surg. 1979;10(12):49–54.PubMed
10.
11.
Fukumasu H, Blaylock R, Veasy LG, Pons AB, Nielsen SD, Lawson JL, Kolff WJ. Intra-aortic balloon pumping device for infants. Clin Cardiol. 1979;2(5):348–53.PubMedCrossRef
12.
Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999;20(6):761–87.PubMed
13.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16(1):3–34.PubMed
14.
Ranke MB. Insulin-like growth factor binding-protein-3 (IGFBP-3). Best Pract Res Clin Endocrinol Metab. 2015;29(5):701–11.PubMedCrossRef
15.
Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem. 2000;275(24):18574–80.PubMedCrossRef
16.
Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun. 2000;278(3):511–5.PubMedCrossRef
17.
Irwin JC, Suen LF, Cheng BH, Martin R, Cannon P, Deal CL, Giudice LC. Human placental trophoblasts secrete a disintegrin metalloproteinase very similar to the insulin-like growth factor binding protein-3 protease in human pregnancy serum. Endocrinology. 2000;141(2):666–74.PubMedCrossRef
18.
Giudice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG. Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: effects of a pregnancy-associated serum protease activity. J Clin Endocrinol Metab. 1990;71(4):806–16.PubMedCrossRef
19.
Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM12 levels in Down and Edwards’ syndrome pregnancies at 9–12 weeks’ gestation. Prenat Diagn. 2006;26(8):689–91.PubMedCrossRef
20.
Matwejew E, Cowans NJ, Stamatopoulou A, Spencer K, von Kaisenberg CS. Maternal serum ADAM-12 as a potential marker for different adverse pregnancy outcomes. Fetal Diagn Ther. 2010;27(1):32–9.PubMedCrossRef
21.
Spencer K, Cowans NJ. ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy. J Matern Fetal Neonatal Med. 2007;20(9):645–50.PubMedCrossRef
22.
Bunn RC, Fowlkes JL. Insulin-like growth factor binding protein proteolysis. Trends Endocrinol Metab. 2003;14(4):176–81.PubMedCrossRef
23.
Hossenlopp P, Segovia B, Lassarre C, Roghani M, Bredon M, Binoux M. Evidence of enzymatic degradation of insulin-like growth factor-binding proteins in the 150K complex during pregnancy. J Clin Endocrinol Metab. 1990;71(4):797–805.PubMedCrossRef
24.
Kokozidou M, Drewlo S, Bartz C, Raven G, Brandenburg LO, Wruck CJ, Pufe T. Complex patterns of ADAM12 mRNA and protein splice variants in the human placenta. Ann Anat. 2011;193(2):142–8.PubMedCrossRef
25.
Gebert CA, Park SH, Waxman DJ. Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation. Mol Endocrinol. 1997;11(4):400–14.PubMedCrossRef
26.
Kloth MT, Catling AD, Silva CM. Novel activation of STAT5b in response to epidermal growth factor. J Biol Chem. 2002;277(10):8693–701.PubMedCrossRef
27.
Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997;11(2):179–86.PubMedCrossRef
28.
Gan XW, Wang WS, Lu JW, Ling LJ, Zhou Q, Zhang HJ, Ying H, Sun K. De novo Synthesis of SAA1 in the Placenta Participates in Parturition. Front Immunol. 2020;11:1038.PubMedPubMedCentralCrossRef
29.
Lu J, Wang W, Mi Y, Zhang C, Ying H, Wang L, Wang Y, Myatt L, Sun K. AKAP95-mediated nuclear anchoring of PKA mediates cortisol-induced PTGS2 expression in human amnion fibroblasts. Sci Signal. 2017;10(506):eaac6160.PubMedCrossRef
30.
Wang W, Guo C, Zhu P, Lu J, Li W, Liu C, Xie H, Myatt L, Chen ZJ, Sun K. Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition. Sci Signal. 2015;8(400):ra106.PubMedCrossRef
31.
32.
Han VK, Bassett N, Walton J, Challis JR. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 1996;81(7):2680–93.PubMed
33.
Giudice LC, Conover CA, Bale L, Faessen GH, Ilg K, Sun I, Imani B, Suen LF, Irwin JC, Christiansen M, et al. Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. J Clin Endocrinol Metab. 2002;87(5):2359–66.PubMedCrossRef
34.
Gupta MB, Abu Shehab M, Nygard K, Biggar K, Singal SS, Santoro N, Powell TL, Jansson T. IUGR is associated with marked hyperphosphorylation of decidual and maternal plasma IGFBP-1. J Clin Endocrinol Metab. 2019;104(2):408–22.PubMedCrossRef
35.
Rogers J, Wiltrout L, Nanu L, Fant ME. Developmentally regulated expression of IGF binding protein-3 (IGFBP-3) in human placental fibroblasts: effect of exogenous IGFBP-3 on IGF-1 action. Regul Pept. 1996;61(3):189–95.PubMedCrossRef
36.
37.
Ray BK, Dhar S, Shakya A, Ray A. Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression. Proc Natl Acad Sci USA. 2011;108(1):103–8.PubMedCrossRef
38.
Li Z, Wang Y, Kong L, Yue Z, Ma Y, Chen X. Expression of ADAM12 is regulated by E2F1 in small cell lung cancer. Oncol Rep. 2015;34(6):3231–7.PubMedCrossRef
39.
Ances IG. Serum concentrations of epidermal growth factor in human pregnancy. Am J Obstet Gynecol. 1973;115(3):357–62.PubMedCrossRef
40.
Carson SA, Chase R, Ulep E, Scommegna A, Benveniste R. Ontogenesis and characteristics of epidermal growth factor receptors in human placenta. Am J Obstet Gynecol. 1983;147(8):932–9.PubMedCrossRef
41.
Lai WH, Guyda HJ. Characterization and regulation of epidermal growth factor receptors in human placental cell cultures. J Clin Endocrinol Metab. 1984;58(2):344–52.PubMedCrossRef
42.
Blay J, Hollenberg MD. The nature and function of polypeptide growth factor receptors in the human placenta. J Dev Physiol. 1989;12(5):237–48.PubMed
43.
Maruo T, Mochizuki M. Immunohistochemical localization of epidermal growth factor receptor and myc oncogene product in human placenta: implication for trophoblast proliferation and differentiation. Am J Obstet Gynecol. 1987;156(3):721–7.PubMedCrossRef
44.
Rao CV, Ramani N, Chegini N, Stadig BK, Carman FR Jr, Woost PG, Schultz GS, Cook CL. Topography of human placental receptors for epidermal growth factor. J Biol Chem. 1985;260(3):1705–10.PubMedCrossRef
45.
Jansson T, Skarland H. Maternally administered epidermal growth factor stimulates fetal growth in the rat. Acta Physiol Scand. 1990;138(2):245–6.PubMedCrossRef
46.
Kamei Y, Tsutsumi O, Yamakawa A, Oka Y, Taketani Y, Imaki J. Maternal epidermal growth factor deficiency causes fetal hypoglycemia and intrauterine growth retardation in mice: possible involvement of placental glucose transporter GLUT3 expression. Endocrinology. 1999;140(9):4236–43.PubMedCrossRef
47.
Maruo T, Matsuo H, Otani T, Mochizuki M. Role of epidermal growth factor (EGF) and its receptor in the development of the human placenta. Reprod Fertil Dev. 1995;7(6):1465–70.PubMedCrossRef
48.
Malik A, Pal R, Gupta SK. Interdependence of JAK-STAT and MAPK signaling pathways during EGF-mediated HTR-8/SVneo cell invasion. PLoS ONE. 2017;12(5): e0178269.PubMedPubMedCentralCrossRef
Metadata
Title
Role of EZH2-mediated H3K27me3 in placental ADAM12-S expression: implications for fetoplacental growth
Authors
Ya-nan Zhu
Xiao-wen Gan
Fan Pan
Xiao-tian Ni
Leslie Myatt
Wang-sheng Wang
Kang Sun
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02391-4

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