Bhlhe41, also known as DEC2, is a nuclear transcriptional repressor belonging to the basic helix-loop-helix protein superfamily. It is involved in regulating many physiological processes such as myogenesis, adipogenesis, circadian rhythms, and DNA repair, and is also associated with cell-specific functions like mesenchymal stem cell regulation, tissue-specific macrophage functions, and lymphoid lineage physiology. In cancer, it can act as either a tumor suppressor or an oncogene, influencing processes like cell cycle control, apoptosis, and epithelial-to-mesenchymal transition [3].

In colorectal cancer, silencing of METTL3, which activates the m6A-Bhlhe41-CXCL1 axis, reduced myeloid-derived suppressor cell (MDSC) accumulation, sustained T-cell activation and proliferation, and suppressed tumor growth. This indicates that METTL3 promotes MDSC migration via Bhlhe41-CXCL1/CXCR2 axis [1]. In the context of myocardial infarction, transient appearance of monocyte-derived Bhlhe41+ macrophages in the “developing” infarct zone at day 7 was crucial in suppressing myofibroblast activation, preventing excessive fibrosis, and limiting infarct area expansion [2].

In summary, Bhlhe41 is a key regulator in multiple physiological and disease-related processes. Gene-knockout models in mice have been instrumental in revealing its role in colorectal cancer, where it impacts the immune landscape, and in myocardial infarction, where it contributes to myocardial remodeling. These findings suggest its potential as a therapeutic target in these disease areas.

References:

1. Chen, Huarong, Pan, Yasi, Zhou, Qiming, Kei Wu, William Ka, Yu, Jun. 2022. METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. In Gastroenterology, 163, 891-907. doi:10.1053/j.gastro.2022.06.024. https://pubmed.ncbi.nlm.nih.gov/35700773/

2. Xu, Yue, Jiang, Kai, Su, Fanghua, Yu, Yong, Xiang, Yaozu. 2023. A transient wave of Bhlhe41+ resident macrophages enables remodeling of the developing infarcted myocardium. In Cell reports, 42, 113174. doi:10.1016/j.celrep.2023.113174. https://pubmed.ncbi.nlm.nih.gov/37751357/

3. Bret, Caroline, Desmots-Loyer, Fabienne, Moreaux, Jérôme, Fest, Thierry. 2024. BHLHE41, a transcriptional repressor involved in physiological processes and tumor development. In Cellular oncology (Dordrecht, Netherlands), 48, 43-66. doi:10.1007/s13402-024-00973-3. https://pubmed.ncbi.nlm.nih.gov/39254779/