Hexim1, also known as hexamethylene bis-acetamide inducible 1, is a key protein that acts as a tumor suppressor and is involved in innate immunity regulation. It is a non-coding RNA-dependent transcription regulator. Hexim1 binds to 7SK RNA and inhibits the positive transcription elongation factor (P-TEFb), thus regulating RNA polymerase II (RNAPII) activity. This function places it in pathways related to gene expression control, which are crucial for various biological processes [1,3,4,5].

In human erythropoiesis, HEXIM1 has a central role. Overexpression of HEXIM1 promotes erythroid proliferation and fetal globin expression. It regulates erythroid proliferation by controlling RNAPII pausing at cell cycle checkpoint genes and increasing RNAPII occupancy at genes promoting cycle progression. Genome-wide profiling shows changes in the distribution of GATA-binding factor 1 (GATA1) and RNAPII, especially at the β-globin loci [2].

In an avian alpha-herpesvirus (Anatid herpesvirus 1) infection, HEXIM1 is significantly upregulated. Excessive HEXIM1 promotes viral progeny production, gene expression, and RNAPII recruitment by affecting P-TEFb and RNAPII S2 phosphorylation, while suppressing some host survival-related genes [7]. Also, in breast and prostate cancer, HEXIM1 can inhibit the transcriptional activity of estrogen receptor α (ERα) and androgen receptor (AR), as well as the synthesis of their endogenous ligands by downregulating AKR1C3 [6].

In conclusion, Hexim1 is essential for regulating transcription, especially through its interaction with P-TEFb. Its role in erythropoiesis, viral infections, and cancer highlights its significance in multiple biological processes and disease conditions. Studies on Hexim1, potentially including gene knockout or conditional knockout mouse models in the future, could further elucidate its mechanisms in these areas, providing insights for therapeutic strategies [2,6,7].

References:

1. Michels, Annemieke A, Bensaude, Olivier. 2018. Hexim1, an RNA-controlled protein hub. In Transcription, 9, 262-271. doi:10.1080/21541264.2018.1429836. https://pubmed.ncbi.nlm.nih.gov/29345523/

2. Lv, Xiurui, Murphy, Kristin, Murphy, Zachary, Mohandas, Narla, Steiner, Laurie A. . HEXIM1 is an essential transcription regulator during human erythropoiesis. In Blood, 142, 2198-2215. doi:10.1182/blood.2022019495. https://pubmed.ncbi.nlm.nih.gov/37738561/

3. Dey, Anwesha, Chao, Sheng-Hao, Lane, David P. 2007. HEXIM1 and the control of transcription elongation: from cancer and inflammation to AIDS and cardiac hypertrophy. In Cell cycle (Georgetown, Tex.), 6, 1856-63. doi:. https://pubmed.ncbi.nlm.nih.gov/17671421/

4. Chen, Ruichuan, Yik, Jasper H N, Lew, Qiao Jing, Chao, Sheng-Hao. 2014. Brd4 and HEXIM1: multiple roles in P-TEFb regulation and cancer. In BioMed research international, 2014, 232870. doi:10.1155/2014/232870. https://pubmed.ncbi.nlm.nih.gov/24592384/

5. Fujinaga, Koh, Huang, Fang, Peterlin, B Matija. 2023. P-TEFb: The master regulator of transcription elongation. In Molecular cell, 83, 393-403. doi:10.1016/j.molcel.2022.12.006. https://pubmed.ncbi.nlm.nih.gov/36599353/

6. Mozar, Fitya, Sharma, Vikas, Gorityala, Shashank, Xu, Yan, Montano, Monica M. . Downregulation of Dihydrotestosterone and Estradiol Levels by HEXIM1. In Endocrinology, 163, . doi:10.1210/endocr/bqab236. https://pubmed.ncbi.nlm.nih.gov/34864989/

7. Wu, Ying, Sun, Anyang, Yang, Qiqi, Wu, Zhen, Cheng, Anchun. 2024. An alpha-herpesvirus employs host HEXIM1 to promote viral transcription. In Journal of virology, 98, e0139223. doi:10.1128/jvi.01392-23. https://pubmed.ncbi.nlm.nih.gov/38363111/