SMARCA5, also known as SNF2H, is a core ATPase of the imitation switch (ISWI) chromatin remodeling complex. It plays a crucial role in DNA-templated events such as transcription, DNA replication, and DNA repair by regulating chromatin structure [3,7]. Genetic models, including knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions in various biological processes and disease conditions.

In leukemia, SMARCA5 is responsible for aberrant chromatin accessibility, promoting transcriptional activation of AKR1B1, which reprograms fructose metabolism and is linked to leukemogenesis. Pharmacological inhibition of AKR1B1 shows therapeutic effects in leukemia mice and patient cells [1]. In muscle regeneration, lncMREF interacts with Smarca5 to promote chromatin accessibility, facilitating the up-regulation of myogenic regulators [2]. In B cells, conditional depletion of Smarca5 impairs B cell activation, immunoglobulin class switching, germinal center formation, and ASC differentiation [4]. In the hematopoietic system, different levels of SMARCA5 expression affect hematopoietic stem cell commitment and lineage differentiation [5]. In diabetes, hyperglycemia-suppressed SMARCA5 disrupts transcriptional homeostasis and leads to endothelial dysfunction [6]. In prostate cancer, USP3 stabilizes SMARCA5 through deubiquitination, promoting DNA damage repair and chemotherapy resistance [7].

In summary, SMARCA5 is essential for chromatin remodeling and is involved in multiple biological processes such as cell differentiation, development, and metabolism. KO and CKO mouse models have revealed its significance in diseases including leukemia, muscle-related disorders, B-cell function-related pathologies, diabetes-related endothelial dysfunction, and prostate cancer, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Yu, Peng-Cheng, Hou, Dan, Chang, Binhe, Sun, Xiao-Jian, Wang, Lan. 2024. SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis. In Developmental cell, 59, 1954-1971.e7. doi:10.1016/j.devcel.2024.04.023. https://pubmed.ncbi.nlm.nih.gov/38776924/

2. Lv, Wei, Jiang, Wei, Luo, Hongmei, Xu, Zaiyan, Zuo, Bo. . Long noncoding RNA lncMREF promotes myogenic differentiation and muscle regeneration by interacting with the Smarca5/p300 complex. In Nucleic acids research, 50, 10733-10755. doi:10.1093/nar/gkac854. https://pubmed.ncbi.nlm.nih.gov/36200826/

3. Bomber, Monica L, Wang, Jing, Liu, Qi, Stengel, Kristy R, Hiebert, Scott W. 2023. Human SMARCA5 is continuously required to maintain nucleosome spacing. In Molecular cell, 83, 507-522.e6. doi:10.1016/j.molcel.2022.12.018. https://pubmed.ncbi.nlm.nih.gov/36630954/

4. Stoler-Barak, Liat, Schmiedel, Dominik, Sarusi-Portuguez, Avital, Stopka, Tomas, Shulman, Ziv. 2024. SMARCA5-mediated chromatin remodeling is required for germinal center formation. In The Journal of experimental medicine, 221, . doi:10.1084/jem.20240433. https://pubmed.ncbi.nlm.nih.gov/39297882/

5. Turkova, Tereza, Kokavec, Juraj, Zikmund, Tomas, Cermak, Lukas, Stopka, Tomas. 2024. Differential requirements for Smarca5 expression during hematopoietic stem cell commitment. In Communications biology, 7, 244. doi:10.1038/s42003-024-05917-z. https://pubmed.ncbi.nlm.nih.gov/38424235/

6. Wang, Ju, Zhou, Hui, Shao, Jinhua, Zhang, Shu, Jin, Jing. 2023. Hyperglycemia-Suppressed SMARCA5 Disrupts Transcriptional Homeostasis to Facilitate Endothelial Dysfunction in Diabetes. In Diabetes & metabolism journal, 47, 366-381. doi:10.4093/dmj.2022.0179. https://pubmed.ncbi.nlm.nih.gov/36872061/

7. Li, Sheng, Xiong, Situ, Li, Zhongqi, Xu, Songhui, Fu, Bin. 2024. USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer. In Cell death & disease, 15, 790. doi:10.1038/s41419-024-07117-3. https://pubmed.ncbi.nlm.nih.gov/39500888/