Med27-KO Mouse

MED27, a subunit of the Mediator multiprotein complex, is involved in transcriptional regulation. The Mediator complex usually cooperates with transcription factors in RNA polymerase II-mediated gene transcription. MED27 is crucial for normal biological development and function, and its dysregulation may be associated with various diseases [1,2,3,4,5,6,7,8,9,10].

In neurodevelopment, biallelic MED27 variants lead to a range of phenotypes from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. Features include global developmental delay/intellectual disability, bilateral cataracts, infantile hypotonia, microcephaly, gait ataxia, dystonia, often combined with epilepsy, limb spasticity, facial dysmorphism, and in some cases, death before adulthood. Brain MRI shows cerebellar atrophy, white matter volume loss, pontine hypoplasia, and basal ganglia atrophy with signal alterations [1,4,8].

In cancer, MED27 promotes the progression of breast cancer, melanoma, and adrenal cortical carcinoma. In breast cancer, it targets KLF4 and Sp1; in melanoma, it affects AKT/MAPK and NF-κB/iNOS signaling pathways; in adrenal cortical carcinoma, it influences the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition process [2,3,6,7].

Generation of Med27 floxed mouse lines and subsequent constitutive (cKO) and inducible (icKO) cardiomyocyte-specific Med27 knockout mouse models revealed that ablation of MED27 in developing mouse cardiomyocytes causes embryonic lethality, while deletion in adult cardiomyocytes leads to heart failure and mortality. It is essential for maintaining the stability of the Mediator core in cardiac development and function [9].

In conclusion, MED27 is vital for transcriptional regulation. Its disruption in genetic models, especially KO/CKO mouse models, reveals its significant roles in neurodevelopmental disorders, cancer progression, and cardiac development and function. Understanding MED27 provides insights into the mechanisms of these biological processes and diseases, potentially guiding new therapeutic strategies [1,2,3,4,5,6,7,8,9,10].

References:

1. Maroofian, Reza, Kaiyrzhanov, Rauan, Cali, Elisa, Houlden, Henry, Severino, Mariasavina. . Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. In Brain : a journal of neurology, 146, 5031-5043. doi:10.1093/brain/awad257. https://pubmed.ncbi.nlm.nih.gov/37517035/

2. Wang, Ruozhu, Yu, Wendan, Zhu, Tianhua, Xu, Lingzhi, Deng, Wuguo. 2023. MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4. In Cancer science, 114, 2277-2292. doi:10.1111/cas.15757. https://pubmed.ncbi.nlm.nih.gov/36786527/

3. Wang, Y-H, Huang, J-H, Tu, J-F, Wu, M-H. . MED27 promotes malignant behavior of cells by affecting Sp1 in breast cancer. In European review for medical and pharmacological sciences, 24, 6802-6808. doi:10.26355/eurrev_202006_21669. https://pubmed.ncbi.nlm.nih.gov/32633372/

4. Meng, Linyan, Isohanni, Pirjo, Shao, Yunru, Carroll, Christopher J, Yang, Yaping. 2021. MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia. In Annals of neurology, 89, 828-833. doi:10.1002/ana.26019. https://pubmed.ncbi.nlm.nih.gov/33443317/

5. Reid, Kimberley M, Spaull, Robert, Salian, Smrithi, Harvey, Robert J, Kurian, Manju A. 2022. MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia. In Movement disorders : official journal of the Movement Disorder Society, 37, 2139-2146. doi:10.1002/mds.29147. https://pubmed.ncbi.nlm.nih.gov/35876425/

6. Tang, Ranran, Xu, Xiangdong, Yang, Wenjing, Li, Man, Deng, Wuguo. 2016. MED27 promotes melanoma growth by targeting AKT/MAPK and NF-κB/iNOS signaling pathways. In Cancer letters, 373, 77-87. doi:10.1016/j.canlet.2016.01.005. https://pubmed.ncbi.nlm.nih.gov/26797421/

7. He, Hongchao, Dai, Jun, Yang, Xiaoqun, Sun, Fukang, Zhu, Yu. . Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/β-catenin signaling pathway and the epithelial-mesenchymal transition process. In Biological chemistry, 399, 593-602. doi:10.1515/hsz-2017-0304. https://pubmed.ncbi.nlm.nih.gov/29730647/

8. Wu, Gongao, Lian, Ruofei, Li, Mengchun, Liang, Ruirui, Dong, Yan. 2024. Novel homozygous missense variants in MED27 associated with neurodevelopmental disorder: Clinical and pathogenetic research. In Heliyon, 10, e37258. doi:10.1016/j.heliyon.2024.e37258. https://pubmed.ncbi.nlm.nih.gov/39296199/

9. Zhu, Siting, Chen, Ze'e, Liu, Canzhao, Fang, Xi, Ouyang, Kunfu. 2024. The essential role of MED27 in stabilizing the mediator complex for cardiac development and function. In Life sciences, 356, 123020. doi:10.1016/j.lfs.2024.123020. https://pubmed.ncbi.nlm.nih.gov/39209248/

10. Yan, Zhaoqi, Xu, Yifeng, Li, Keke, Liu, Liangji. 2024. Genetic correlation between smoking behavior and gastroesophageal reflux disease: insights from integrative multi-omics data. In BMC genomics, 25, 642. doi:10.1186/s12864-024-10536-3. https://pubmed.ncbi.nlm.nih.gov/38937676/