Supt16, a component of the facilitates chromatin transcription (FACT) complex, is crucial for chromatin-related processes. FACT is involved in chromatin remodeling during transcription, replication, and DNA repair [3,4,5,6,7,8,9]. Supt16, along with SSRP1, forms the FACT heterodimer, which reorganizes nucleosomes to ensure efficient RNA Pol II elongation and nucleosome integrity [3]. It is associated with multiple pathways, and its study via genetic models provides insights into its in-vivo functions.

Supt16+/- mouse models have been instrumental in understanding its role. In these mice, there are abnormal cognitive and social behaviors, along with a decrease in the number of neurocytes in the cerebral cortex and hippocampus. This is due to the impairment of mouse neural stem cells (mNSCs) in the SVZ, as Supt16 haploinsufficiency affects mNSC proliferation and apoptosis. RNA-seq and chromatic immunoprecipitation sequencing assays show that it disrupts mNSC stemness by inhibiting the MAPK signal pathway [1]. In human pluripotent stem cells derived neural stem cells, Supt16+/- cells exhibit impaired proliferation, cell cycle arrest, and increased apoptosis. RNA-seq analysis reveals that Supt16 haploinsufficiency inhibits the PI3K/AKT/mTOR pathway, leading to increased autophagy and dysregulated expression of proteins related to cell proliferation and apoptosis [2].

In conclusion, Supt16 is essential for processes like neural stem cell self-renewal. Studies using Supt16 KO/CKO mouse models have provided significant insights into its role in neurodevelopmental disorders, highlighting its importance in understanding the pathogenesis of such diseases [1,2].

References:

1. Wang, Junwen, Zhu, Xintong, Dai, Limeng, Bai, Yun, Guo, Hong. . Supt16 haploinsufficiency causes neurodevelopment disorder by disrupting MAPK pathway in neural stem cells. In Human molecular genetics, 32, 860-872. doi:10.1093/hmg/ddac240. https://pubmed.ncbi.nlm.nih.gov/36226587/

2. Wang, Junwen, Wang, Ziyi, Dai, Limeng, Bai, Yun, Guo, Hong. 2023. Supt16 Haploinsufficiency Impairs PI3K/AKT/mTOR/Autophagy Pathway in Human Pluripotent Stem Cells Derived Neural Stem Cells. In International journal of molecular sciences, 24, . doi:10.3390/ijms24033035. https://pubmed.ncbi.nlm.nih.gov/36769360/

3. Mylonas, Constantine, Tessarz, Peter. 2018. Transcriptional repression by FACT is linked to regulation of chromatin accessibility at the promoter of ES cells. In Life science alliance, 1, e201800085. doi:10.26508/lsa.201800085. https://pubmed.ncbi.nlm.nih.gov/30456357/

4. Chen, Fuquan, Zhang, Weiyu, Xie, Dan, Dong, Zhiqiang, Lu, Xinyi. . Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters. In Nucleic acids research, 48, 10211-10225. doi:10.1093/nar/gkaa732. https://pubmed.ncbi.nlm.nih.gov/32894293/

5. Shen, Zuolian, Formosa, Tim, Tantin, Dean. 2018. FACT Inhibition Blocks Induction But Not Maintenance of Pluripotency. In Stem cells and development, 27, 1693-1701. doi:10.1089/scd.2018.0150. https://pubmed.ncbi.nlm.nih.gov/30319048/

6. Husain, Afzal, Begum, Nasim A, Taniguchi, Takako, Kobayashi, Maki, Honjo, Tasuku. 2016. Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability. In Nature communications, 7, 10549. doi:10.1038/ncomms10549. https://pubmed.ncbi.nlm.nih.gov/26842758/

7. Ferri, Federica, Petit, Vanessa, Barroca, Vilma, Romeo, Paul-Henri. 2019. Interplay between FACT subunit SPT16 and TRIM33 can remodel chromatin at macrophage distal regulatory elements. In Epigenetics & chromatin, 12, 46. doi:10.1186/s13072-019-0288-3. https://pubmed.ncbi.nlm.nih.gov/31331374/

8. Kihara, Takanori, Kano, Fumi, Murata, Masayuki. 2007. Modulation of SRF-dependent gene expression by association of SPT16 with MKL1. In Experimental cell research, 314, 629-37. doi:. https://pubmed.ncbi.nlm.nih.gov/18036521/

9. Garcia, Henry, Miecznikowski, Jeffrey C, Safina, Alfiya, Morrison, Carl, Gurova, Katerina V. 2013. Facilitates chromatin transcription complex is an "accelerator" of tumor transformation and potential marker and target of aggressive cancers. In Cell reports, 4, 159-73. doi:10.1016/j.celrep.2013.06.013. https://pubmed.ncbi.nlm.nih.gov/23831030/