TCL1A, a novel transcription factor and a coregulator of nuclear factor kB p65: Single nucleotide polymorphism and estrogen dependences

Ming Fen Ho, Edroaldo Lummertz da Rocha, Cheng Zhang, James N. Ingle, Paul E. Goss, Lois E. Shepherd, Michiaki Kubo, Liewei Wang, Hu Li, Richard M. Weinshilboum

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T-cell leukemia 1A (TCL1A) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E2) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be “reversed” by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E2-dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E2 in a SNP-dependent fashion. Even more striking, nuclear factor-kB (NF-kB) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E2-dependent fashion—a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF-kB p65, an important immune system transcription factor.

元の言語English
ページ(範囲)700-710
ページ数11
ジャーナルJournal of Pharmacology and Experimental Therapeutics
365
発行部数3
DOI
出版物ステータスPublished - 06-2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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    Ho, M. F., Lummertz da Rocha, E., Zhang, C., Ingle, J. N., Goss, P. E., Shepherd, L. E., Kubo, M., Wang, L., Li, H., & Weinshilboum, R. M. (2018). TCL1A, a novel transcription factor and a coregulator of nuclear factor kB p65: Single nucleotide polymorphism and estrogen dependences. Journal of Pharmacology and Experimental Therapeutics, 365(3), 700-710. https://doi.org/10.1124/jpet.118.247718