CBX5, also known as HP1α, is an epigenetic regulatory protein. It is a methyl reader that interprets H3K9me3 marks, which are mediated by H3K9 methyltransferases. CBX5 is involved in maintaining chromatin state, and is associated with processes like gene silencing through its role in heterochromatin formation [5]. It participates in multiple biological pathways, and its dysregulation can impact various cellular functions.

In myeloid leukemia, the RNA binding proteins RBMX and RBMXL1 directly bind to mRNAs, affect the transcription of multiple loci including CBX5, and control its nascent transcription. Forced CBX5 expression rescued the effects of RBMX/L1 depletion on cell growth and apoptosis, indicating that RBMX/L1 control leukemia cell survival by regulating chromatin state through CBX5 [1]. In lung cancer, loss of CBX5 drives EGFR inhibitor resistance. CBX5 loss leads to increased E2F1 expression, which stimulates the anti-apoptotic gene BIRC5, attenuating apoptosis induction following EGFRi treatment [2]. In periodontitis, Porphyromonas gingivalis OMVs contain msRNA sRNA45033 that targets CBX5, and CBX5 regulates apoptosis through the methylation of p53 DNA [3]. In lung fibrosis, the CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation. Both TGFβ and increased matrix stiffness inhibit PGC1α expression in lung fibroblasts through the CBX5/G9a pathway [4].

In summary, CBX5 plays essential roles in maintaining chromatin state and regulating gene expression. Studies using gene-related models, although not always specifically KO/CKO mouse models in these references, have revealed its significance in diseases such as myeloid leukemia, lung cancer, periodontitis, and lung fibrosis. Understanding CBX5's functions provides insights into the underlying mechanisms of these diseases, potentially leading to new therapeutic strategies.

References:

1. Prieto, Camila, Nguyen, Diu T T, Liu, Zhaoqi, Rabadan, Raul, Kharas, Michael G. 2021. Transcriptional control of CBX5 by the RNA binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia. In Nature cancer, 2, 741-757. doi:10.1038/s43018-021-00220-w. https://pubmed.ncbi.nlm.nih.gov/34458856/

2. Bugide, Suresh, Edwards, Yvonne J K, Gupta, Romi, Green, Michael R, Wajapeyee, Narendra. 2023. CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2218118120. doi:10.1073/pnas.2218118120. https://pubmed.ncbi.nlm.nih.gov/36652476/

3. Fan, Ruyi, Zhou, Yi, Chen, Xu, Wang, Xiaoqian, Xu, Yan. 2023. Porphyromonas gingivalis Outer Membrane Vesicles Promote Apoptosis via msRNA-Regulated DNA Methylation in Periodontitis. In Microbiology spectrum, 11, e0328822. doi:10.1128/spectrum.03288-22. https://pubmed.ncbi.nlm.nih.gov/36629433/

4. Ligresti, Giovanni, Caporarello, Nunzia, Meridew, Jeffrey A, Urrutia, Raul A, Tschumperlin, Daniel J. 2019. CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. In JCI insight, 5, . doi:10.1172/jci.insight.127111. https://pubmed.ncbi.nlm.nih.gov/31095524/

5. van Wijnen, Andre J, Bagheri, Leila, Badreldin, Amr A, Paradise, Christopher R, Wu, Zhong. 2020. Biological functions of chromobox (CBX) proteins in stem cell self-renewal, lineage-commitment, cancer and development. In Bone, 143, 115659. doi:10.1016/j.bone.2020.115659. https://pubmed.ncbi.nlm.nih.gov/32979540/