Hsf4, Heat Shock Transcription Factor 4, is a transcription factor that plays crucial roles in multiple biological processes. It is involved in the heat stress response in maize [1], lens terminal differentiation [2,6,7,8,9], and is associated with diseases like congenital cataracts [2,5,6,7,8,9], colorectal cancer [3], and ultraviolet-induced inflammatory skin injury [4]. In the heat stress response of maize, it is regulated by ZmHsf20 and promotes the heat stress response by directly activating ZmCesA2 transcription [1].

In lens terminal differentiation, Hsf4del42 mutant mice, a form of gene knockout model, display delayed organelle clearance and impaired autophagic degradation in lens fibers, indicating Hsf4's role in facilitating organelle degradation likely by transcriptionally activating autophagy [2]. In zebrafish hsf4 null mutants, there are early-onset cataracts, over-proliferation of lens epithelial cells, and interrupted terminal differentiation of lens fiber cells, suggesting Hsf4 promotes lens fiber cell differentiation by activating p53 and its downstream regulators [8].

In summary, Hsf4 is essential for the heat stress response in plants and lens development in animals. Gene knockout models in mice and zebrafish have revealed its key functions in these processes, and its association with congenital cataracts, colorectal cancer, and skin inflammation. Understanding Hsf4 can provide insights into disease mechanisms and potential therapeutic strategies for related diseases.

References:

1. Li, Ze, Li, Zerui, Ji, Yulong, Le, Jie, Zhang, Mei. . The heat shock factor 20-HSF4-cellulose synthase A2 module regulates heat stress tolerance in maize. In The Plant cell, 36, 2652-2667. doi:10.1093/plcell/koae106. https://pubmed.ncbi.nlm.nih.gov/38573521/

2. Zhang, Jing, Jiang, Ning, Du, Chunxiao, Hu, Yanzhong, Cui, Xiukun. . HSF4 Transcriptionally Activates Autophagy by Regulating ATG9a During Lens Terminal Differentiation. In Investigative ophthalmology & visual science, 64, 5. doi:10.1167/iovs.64.7.5. https://pubmed.ncbi.nlm.nih.gov/37266953/

3. Zhang, Wenjing, Zhang, Xuelian, Cheng, Peng, Guo, Qiang, Zhang, Yu. 2022. HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET. In Molecular and cellular biochemistry, 478, 1141-1150. doi:10.1007/s11010-022-04582-2. https://pubmed.ncbi.nlm.nih.gov/36229759/

4. Feng, Yi-Qian, Zhang, Heng, Han, Jing-Xia, Liu, Hui-Juan, Sun, Tao. . HSF4/COIL complex-dependent R-loop mediates ultraviolet-induced inflammatory skin injury. In Clinical and translational medicine, 13, e1336. doi:10.1002/ctm2.1336. https://pubmed.ncbi.nlm.nih.gov/37461263/

5. Anand, Deepti, Agrawal, Smriti A, Slavotinek, Anne, Lachke, Salil A. 2018. Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. In Human mutation, 39, 471-494. doi:10.1002/humu.23395. https://pubmed.ncbi.nlm.nih.gov/29314435/

6. Liao, Shengjie, Qu, Zhen, Li, Linqiang, Huang, Mi, Li, Duanzhuo. 2018. HSF4 transcriptional regulates HMOX-1 expression in HLECs. In Gene, 655, 30-34. doi:10.1016/j.gene.2018.02.033. https://pubmed.ncbi.nlm.nih.gov/29454088/

7. Huang, Mi, Li, Duanzhuo, Huang, Yuwen, Li, David Wan-Cheng, Liu, Mugen. 2015. HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53. In Biochimica et biophysica acta, 1853, 1808-17. doi:10.1016/j.bbamcr.2015.04.018. https://pubmed.ncbi.nlm.nih.gov/25940838/

8. Gao, Meng, Huang, Yuwen, Wang, Ling, Li, David Wan-Cheng, Liu, Mugen. 2017. HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators. In Cell death & disease, 8, e3082. doi:10.1038/cddis.2017.478. https://pubmed.ncbi.nlm.nih.gov/28981088/

9. Cui, Xiukun, Wang, Lei, Zhang, Jing, Tang, Zhaohui, Liu, Mugen. 2013. HSF4 regulates DLAD expression and promotes lens de-nucleation. In Biochimica et biophysica acta, 1832, 1167-72. doi:10.1016/j.bbadis.2013.03.007. https://pubmed.ncbi.nlm.nih.gov/23507146/