Abstract
CD45, a common leukocyte antigen expressed on the surface of all nucleated hematopoietic cells, indicates the developmental stage and functional status of lymphocytes by its alternative splicing isoforms. Estrogen is correlated with the immune activity of lymphocytes and is involved in the sex bias of several human autoimmune diseases, but the effect of estrogen on the expression of the CD45 splicing isoforms remains unknown. In the present study, a potential estrogen response element was identified on the opposite strand of the CD45 gene by bioinformatics software prediction. The results from RT-qPCR results showed that the expression levels of CD45RO isoform and CD45 antisense RNA were increased after the lymphocytes were treated with 10 nM 17beta-estradiol, and this effect of 17beta-estradiol was reversed when the lymphocytes were cotreated with an estrogen receptor antagonist. Moreover, bisulfite sequencing PCR showed that CD45 DNA methylation in lymphocytes was increased after the treatment with 10 nM 17beta-estradiol. In conclusion, estradiol regulated the expression of CD45 in an estrogen receptor-dependent manner and was associated with CD45 antisense RNA and DNA methylation. The results helped elucidate the regulatory mechanism of the expression of CD45 isoforms and the correlation between estrogen levels and immune activity in females.
This is a preview of subscription content, log in via an institution to check access.
References
Moulton VR (2018) Sex hormones in acquired immunity and autoimmune disease. Front Immunol 9:2279
Rubinow KB (2018) An intracrine view of sex steroids, immunity, and metabolic regulation. Mol Metab 15:92–103
Khan D, Ansar Ahmed S (2015) The immune system is a natural target for estrogen action: opposing effects of estrogen in two prototypical autoimmune diseases. Front Immunol 6:635
Purnamawati K, Ong JA, Deshpande S et al (2018) The importance of sex stratification in autoimmune disease biomarker research: a systematic review. Front Immunol 9:1208
Macedo EA, Appenzeller S, Costallat LT (2016) Gender differences in systemic lupus erythematosus concerning anxiety, depression and quality of life. Lupus 25(12):1315–1327
Hermiston ML, Xu Z, Weiss A (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 21:107–137
Courtney AH, Shvets AA, Lu W (2019) CD45 functions as a signaling gatekeeper in T cells. Sci Signal 12(604):eaaw8151
Zikherman J, Weiss A (2008) Alternative splicing of CD45: the tip of the iceberg. Immunity 29(6):839–841
Chang VT, Fernandes RA, Ganzinger KA et al (2016) Initiation of T cell signaling by CD45 segregation at 'close contacts'. Nat Immunol 17(5):574–582
Razvag Y, Neve-Oz Y, Sajman J et al (2018) Nanoscale kinetic segregation of TCR and CD45 in engaged microvilli facilitates early T cell activation. Nat Commun 9(1):732
Rheinlander A, Schraven B, Bommhardt U (2018) CD45 in human physiology and clinical medicine. Immunol Lett 196:22–32
Tchilian EZ, Beverley PC (2006) Altered CD45 expression and disease. Trends Immunol 27(3):146–153
Rong J, Yin J, Su Z (2015) Natural antisense RNAs are involved in the regulation of CD45 expression in autoimmune diseases. Lupus 24(3):235–239
Shukla S, Kavak E, Gregory M et al (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479(7371):74–79
Davis-Turak J, Johnson TL, Hoffmann A (2018) Mathematical modeling identifies potential gene structure determinants of co-transcriptional control of alternative pre-mRNA splicing. Nucleic Acids Res 46(20):10598–10607
Hedrich CM, Tsokos GC (2011) Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases. Trends Mol Med 17(12):714–724
Stone A, Zotenko E, Locke WJ et al (2015) DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nat Commun 6:7758
Dumasia K, Zotenko E, Locke WJ et al (2017) Estrogen signaling, through estrogen receptor beta, regulates DNA methylation and its machinery in male germ line in adult rats. Epigenetics 12(6):476–483
Khorkova O, Myers AJ, Hsiao J et al (2014) Natural antisense transcripts. Hum Mol Genet 23(R1):54–63
Latge G, Poulet C, Bours V et al (2018) Natural antisense transcripts: molecular mechanisms and implications in breast cancers. Int J Mol Sci 19(1):E123
Schüler-Toprak S, Häring J, Inwald EC et al (2016) Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro. BMC Cancer 16(1):951
Li D, Chen J, Ai Y et al (2019) Estrogen-related hormones induce apoptosis by stabilizing schlafen-12 protein turnover. Mol Cell 75(6):1103–1116
Chandrasekharan S, Kandasamy KK, Dayalan P et al (2013) Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: role of transcription factors. Biochem Biophys Res Commun 437(3):475–481
Zhang L, Ma Y, Liu M et al (2019) The effects of various estrogen doses on the proliferation and differentiation of cultured neural stem cells. Gen Physiol Biophys 38(5):417–425
Funding
This study was funded by National Natural Science Foundation of China (No. 31870745) and Natural Science Foundation of Guangdong Province, China (No. 2018A0303130153).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhang, T., Dong, Z., Cai, H. et al. Estradiol regulates the expression of CD45 splicing isoforms in lymphocytes. Mol Biol Rep 47, 3025–3030 (2020). https://doi.org/10.1007/s11033-020-05373-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-020-05373-y