Atf7ip, also known as activating transcription factor 7 interacting protein, is an epigenetic regulator that plays crucial roles in various biological processes. It is closely associated with the Setdb1 methyltransferase, and together they are involved in pathways such as histone modification and chromatin remodeling, which are vital for maintaining normal cellular functions and development [1,2,3,4,5,6,7,8].

In zebrafish mutants deficient in Atf7ip, there is excessive myeloid differentiation with impaired hematopoietic stem and progenitor cell (HSPC) expansion, leading to a decline in T cells and the erythroid lineage. Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling, preventing premature differentiation of HSPCs into the myeloid lineage [1]. In mice with T cell-specific deletion of Atf7ip, there are enhanced CD8+ T cell effector and memory responses due to increased Il7r and Il2 expression, as Atf7ip represses these genes through H3K9me3 deposition at relevant loci [3]. Also, Th17 differentiation is impaired in Atf7ip-deficient T cells, secondary to aberrant overproduction of IL-2 [5]. In MC3T3-E1 cells, overexpression of Atf7ip impairs osteoblast differentiation, while its depletion promotes it, and Atf7ip-deleted mice in osteoblasts show more bone formation [2]. Disrupting Atf7ip in tumor cells restores tumor antigen expression, augmenting tumor immunogenicity [7].

In summary, Atf7ip, often in conjunction with Setdb1, is essential for maintaining the balance of cell differentiation, immune responses, and tumor antigen expression. Studies using gene knockout models in zebrafish and mice have revealed its role in hematopoiesis, T cell function, osteoblast differentiation, and tumor immunity, providing insights into potential interventions for hematological malignancies, bone-related diseases, and cancer immunotherapy [1,2,3,5,7].

References:

1. Wu, Jiaxin, Li, Juan, Chen, Kang, Xie, Peng, Zhong, Tao P. 2022. Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2209062120. doi:10.1073/pnas.2209062120. https://pubmed.ncbi.nlm.nih.gov/36577070/

2. Hu, Guoqin, Shi, Xian, Qu, Xiuxia, Liu, Huanliang, Wu, Yu. 2023. Atf7ip Inhibits Osteoblast Differentiation via Negative Regulation of the Sp7 Transcription Factor. In International journal of molecular sciences, 24, . doi:10.3390/ijms24054305. https://pubmed.ncbi.nlm.nih.gov/36901736/

3. Sin, Jun Hyung, Kashyap, Sujit, Acenas, Dante, Matloubian, Mehrdad, Waterfield, Michael R. 2022. ATF7ip Targets Transposable Elements for H3K9me3 Deposition to Modify CD8+ T Cell Effector and Memory Responses. In Journal of immunology (Baltimore, Md. : 1950), 208, 1155-1169. doi:10.4049/jimmunol.2100996. https://pubmed.ncbi.nlm.nih.gov/35110421/

4. Tsusaka, Takeshi, Shimura, Chikako, Shinkai, Yoichi. 2019. ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination. In EMBO reports, 20, e48297. doi:10.15252/embr.201948297. https://pubmed.ncbi.nlm.nih.gov/31576654/

5. Sin, Jun Hyung, Zuckerman, Cassandra, Cortez, Jessica T, Anderson, Mark S, Waterfield, Michael R. 2019. The epigenetic regulator ATF7ip inhibits Il2 expression, regulating Th17 responses. In The Journal of experimental medicine, 216, 2024-2037. doi:10.1084/jem.20182316. https://pubmed.ncbi.nlm.nih.gov/31217192/

6. Kariapper, Leena, Marathe, Ila A, Niesman, Ashley B, Wysocki, Vicki H, Worden, Evan J. 2024. Setdb1 and Atf7IP form a hetero-trimeric complex that blocks Setdb1 nuclear export. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.12.23.630145. https://pubmed.ncbi.nlm.nih.gov/39764026/

7. Hu, Hai, Khodadadi-Jamayran, Alireza, Dolgalev, Igor, Li, Fei, Wong, Kwok-Kin. 2021. Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity. In Cancer immunology research, 9, 1298-1315. doi:10.1158/2326-6066.CIR-21-0543. https://pubmed.ncbi.nlm.nih.gov/34462284/

8. Timms, Richard T, Tchasovnikarova, Iva A, Antrobus, Robin, Dougan, Gordon, Lehner, Paul J. . ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex. In Cell reports, 17, 653-659. doi:10.1016/j.celrep.2016.09.050. https://pubmed.ncbi.nlm.nih.gov/27732843/