Jmjd4, or Jumonji C domain-containing demethylase 4, is a protein-encoding gene. Initially identified as a histone demethylase, it has diverse functions including protein hydroxylation and is involved in various biological processes. It may participate in regulating mRNA translation and is a part of the JMJD protein family, which has been linked to many cardiovascular diseases [1,7].

In a study of dilated cardiomyopathy (DCM), expression of Jmjd4 was significantly decreased in patients' hearts. Cardiomyocyte-specific deletion of Jmjd4 in mice led to spontaneous DCM with severely impaired mitochondrial respiration. Mechanistically, Jmjd4 interacted with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which was dependent on hydroxylation of K66 of Pkm2 by Jmjd4 [1]. In another study, hepatocyte-specific RIG-I knockout mice were used to explore the role of JMJD4-demethylated RIG-I in hepatic steatosis and carcinogenesis. It was found that JMJD4-demethylated RIG-I prevented both necroinflammation and NASH-induced hepatocarcinogenesis [2]. Also, Jmjd4-knockout mice demonstrated that JMJD4 is dispensable in murine development [3]. In cancer research, JMJD4 promotes tumor progression via inhibition of the PDCD5-TP53 pathway, and high expression of JMJD4 is associated with poor prognosis in colon and lung cancer patients [4]. High JMJD4 expression may be a prognostic marker in renal cell carcinoma as it promotes invasion, cloning, and proliferation of renal cancer cells [5,6].

In conclusion, Jmjd4 plays important roles in maintaining metabolic homeostasis in cardiomyocytes, preventing hepatic steatosis and carcinogenesis, and is involved in tumor progression. Mouse models, especially gene knockout and conditional knockout models, have been crucial in revealing these functions in the context of dilated cardiomyopathy, hepatic diseases, and cancer. These findings contribute to understanding the biological functions of Jmjd4 and may provide potential therapeutic targets for related diseases.

References:

1. Tang, Yansong, Feng, Mengying, Su, Yang, Wei, Ke, Xu, Dachun. 2023. Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy. In Circulation, 147, 1684-1704. doi:10.1161/CIRCULATIONAHA.123.064121. https://pubmed.ncbi.nlm.nih.gov/37066795/

2. Li, Zhenyang, Zhou, Ye, Jia, Kaiwei, Cao, Xuetao, Hou, Jin. 2022. JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis. In Journal of hematology & oncology, 15, 161. doi:10.1186/s13045-022-01381-6. https://pubmed.ncbi.nlm.nih.gov/36333807/

3. Yoo, Hyunjin, Son, Dabin, Lee, Young Jae, Hong, Kwonho. 2016. Mouse JMJD4 is dispensable for embryogenesis. In Molecular reproduction and development, 83, 588-93. doi:10.1002/mrd.22654. https://pubmed.ncbi.nlm.nih.gov/27147518/

4. Kim, Hyunsik, Jang, Subhin, Lee, Soo Yeon, Park, Soo-Yeon, Yoon, Ho-Geun. . JMJD4 promotes tumor progression via inhibition of the PDCD5-TP53 pathway. In BMB reports, 58, 64-69. doi:. https://pubmed.ncbi.nlm.nih.gov/39567206/

5. Yan, Hao, Bao, Yewei, Lin, Zongming. 2021. High Expression of JMJD4 Is a Potential Diagnostic and Prognostic Marker of Renal Cell Carcinoma. In Disease markers, 2021, 9573540. doi:10.1155/2021/9573540. https://pubmed.ncbi.nlm.nih.gov/34980950/

6. Elsayed, Walid S H, Harb, Ola A, Alabiad, Mohamed Ali, Abdelhady, Waleed A, Ali, Ramadan M. 2023. Protein Expression of NEK2, JMJD4, and REST in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical, Pathological, and Prognostic Findings. In Iranian journal of pathology, 18, 180-192. doi:10.30699/IJP.2023.1974154.3022. https://pubmed.ncbi.nlm.nih.gov/37600577/

7. Oh, Sangphil, Shin, Sook, Janknecht, Ralf. 2019. The small members of the JMJD protein family: Enzymatic jewels or jinxes? In Biochimica et biophysica acta. Reviews on cancer, 1871, 406-418. doi:10.1016/j.bbcan.2019.04.002. https://pubmed.ncbi.nlm.nih.gov/31034925/