SOX17 explained

SRY-box 17 is a protein that in humans is encoded by the SOX17 gene.^[1]

Regulation at the human SOX17 locus

The gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors, located on Chromosome 8 q11.23. Its gene body is isolated within a CTCF loop domain.^{[2] [3] [4]} Approximately 230 kb upstream of SOX17 it has been identified a tissue specific differentially (hypo-)methylated region (DMR), which consists of SOX17 regulatory elements.^{[5] [6]} The DMR in particular bears the most distal definitive endoderm-specific enhancer at the SOX17 locus.^[7] SOX17 itself has recently been defined as so called topologically insulated gene (TIG). TIGs per definition are single protein coding genes (PCGs) within CTCF loop domains, that are mainly enriched in developmental regulators and suggested to be very tightly controlled via their 3D loop-domain architecture.^[8]

Function in development

SOX17 is involved in the regulation of vertebrate embryonic development and in the determination of the endodermal cell fate. The encoded protein acts downstream of TGF beta signaling (Activin) and canonical WNT signaling (Wnt3a).^{[9] [10]} Especially the correct phosphorylation of SMAD2/3 within the respective cell cycle (early G1 phase) is crucial for the activation of cardinal endodermal genes (e.g. SOX17) to further enter the definitive endodermal lineage.^[11] Besides that, perturbation of the SOX17 centromertic CTCF-boundary in early definitive endoderm differentiation, leads to massive developmental failure and a so-called mes-endodermal like trapped cell-state, which can be rescued by ectopic SOX17 expression.^[12] In Xenopus gastrulae it has been shown that SOX17 modifies Wnt responses, where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between SOX17 and β-catenin/Tcf transcriptional complexes.^[13]

Further reading

• Zhang W, Glöckner SC, Guo M, Machida EO, Wang DH, Easwaran H, Van Neste L, Herman JG, Schuebel KE, Watkins DN, Ahuja N, Baylin SB . James G. . Nita Ahuja . Stephen B. Baylin Herman . 6 . Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer . Cancer Research . 68 . 8 . 2764–72 . April 2008 . 18413743 . 2823123 . 10.1158/0008-5472.CAN-07-6349 .
• Patterson ES, Addis RC, Shamblott MJ, Gearhart JD . SOX17 directly activates Zfp202 transcription during in vitro endoderm differentiation . Physiological Genomics . 34 . 3 . 277–84 . August 2008 . 18523156 . 10.1152/physiolgenomics.90236.2008 .
• Ferrell RE, Kimak MA, Lawrence EC, Finegold DN . Candidate gene analysis in primary lymphedema . Lymphatic Research and Biology . 6 . 2 . 69–76 . 2008 . 18564921 . 10.1089/lrb.2007.1022 .
• Séguin CA, Draper JS, Nagy A, Rossant J . Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells . Cell Stem Cell . 3 . 2 . 182–95 . August 2008 . 18682240 . 10.1016/j.stem.2008.06.018 . free .
• Semb H . Expandable endodermal progenitors: new tools to explore endoderm and its derivatives . Cell Stem Cell . 3 . 4 . 355–6 . October 2008 . 18940723 . 10.1016/j.stem.2008.09.010 . free .
• Fu DY, Wang ZM, Wang BL, Shen ZZ, Huang W, Shao ZM . Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer . Breast Cancer Research and Treatment . 119 . 3 . 601–12 . February 2010 . 19301122 . 10.1007/s10549-009-0339-8 . 8614063 .
• Nonaka D . Differential expression of SOX2 and SOX17 in testicular germ cell tumors . American Journal of Clinical Pathology . 131 . 5 . 731–6 . May 2009 . 19369635 . 10.1309/AJCP7MNCNBCRN8NO . free .
• Du YC, Oshima H, Oguma K, Kitamura T, Itadani H, Fujimura T, Piao YS, Yoshimoto T, Minamoto T, Kotani H, Taketo MM, Oshima M . 6 . Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis . Gastroenterology . 137 . 4 . 1346–57 . October 2009 . 19549530 . 10.1053/j.gastro.2009.06.041 . free . 2297/25144 . 6296792 .
• Stefanovic S, Abboud N, Désilets S, Nury D, Cowan C, Pucéat M . Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate . The Journal of Cell Biology . 186 . 5 . 665–73 . September 2009 . 19736317 . 2742180 . 10.1083/jcb.200901040 .
• MacCarthy CM, Malik V, Wu G, et al., & Velychko S (September 2022). "Enhancing Sox/Oct cooperativity induces higher-grade developmental reset". bioRxiv.

Notes and References

1. Web site: Entrez Gene: SRY-box 17. 2017-09-07.
2. Rao SS, Huang SC, Glenn St Hilaire B, Engreitz JM, Perez EM, Kieffer-Kwon KR, Sanborn AL, Johnstone SE, Bascom GD, Bochkov ID, Huang X, Shamim MS, Shin J, Turner D, Ye Z, Omer AD, Robinson JT, Schlick T, Bernstein BE, Casellas R, Lander ES, Aiden EL . 6 . Cohesin Loss Eliminates All Loop Domains . Cell . 171 . 2 . 305–320.e24 . October 2017 . 28985562 . 10.1016/j.cell.2017.09.026 . 5846482 . 1721.1/118942 . free .
3. Szabo Q, Bantignies F, Cavalli G . Principles of genome folding into topologically associating domains . Science Advances . 5 . 4 . eaaw1668 . April 2019 . 30989119 . 10.1126/sciadv.aaw1668 . 6457944 . 2019SciA....5.1668S .
4. Wu. Hua-Jun. Landshammer. Alexandro. Stamenova. Elena K.. Bolondi. Adriano. Kretzmer. Helene. Meissner. Alexander. Michor. Franziska. 2021-08-12. Topological isolation of developmental regulators in mammalian genomes. Nature Communications. en. 12. 1. 4897. 34385432. 10.1038/s41467-021-24951-7. 2041-1723. 8361032. 2021NatCo..12.4897W .
5. Tsankov AM, Gu H, Akopian V, Ziller MJ, Donaghey J, Amit I, Gnirke A, Meissner A . 6 . Transcription factor binding dynamics during human ES cell differentiation . Nature . 518 . 7539 . 344–9 . February 2015 . 25693565 . 10.1038/nature14233 . 4499331 . 2015Natur.518..344T .
6. Wu. Hua-Jun. Landshammer. Alexandro. Stamenova. Elena K.. Bolondi. Adriano. Kretzmer. Helene. Meissner. Alexander. Michor. Franziska. 2021-08-12. Topological isolation of developmental regulators in mammalian genomes. Nature Communications. en. 12. 1. 4897. 10.1038/s41467-021-24951-7. 34385432 . 2041-1723. 8361032. 2021NatCo..12.4897W .
7. Wu. Hua-Jun. Landshammer. Alexandro. Stamenova. Elena K.. Bolondi. Adriano. Kretzmer. Helene. Meissner. Alexander. Michor. Franziska. 2021-08-12. Topological isolation of developmental regulators in mammalian genomes. Nature Communications. en. 12. 1. 4897. 10.1038/s41467-021-24951-7. 34385432 . 2041-1723. 8361032. 2021NatCo..12.4897W .
8. Wu. Hua-Jun. Landshammer. Alexandro. Stamenova. Elena K.. Bolondi. Adriano. Kretzmer. Helene. Meissner. Alexander. Michor. Franziska. 2021-08-12. Topological isolation of developmental regulators in mammalian genomes. Nature Communications. en. 12. 1. 4897. 10.1038/s41467-021-24951-7. 34385432 . 2041-1723. 8361032. 2021NatCo..12.4897W .
9. Engert S, Burtscher I, Liao WP, Dulev S, Schotta G, Lickert H . Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse . Development . 140 . 15 . 3128–38 . August 2013 . 23824574 . 10.1242/dev.088765 . free .
10. Mukherjee S, Chaturvedi P, Rankin SA, Fish MB, Wlizla M, Paraiso KD, MacDonald M, Chen X, Weirauch MT, Blitz IL, Cho KW, Zorn AM . 6 . Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network . eLife . 9 . e58029 . September 2020 . 32894225 . 10.7554/eLife.58029 . Carole . Morrisey . Edward E . LaBonne . 7498262 . free .
11. Pauklin S, Vallier L . The cell-cycle state of stem cells determines cell fate propensity . English . Cell . 155 . 1 . 135–47 . September 2013 . 24074866 . 10.1016/j.cell.2013.08.031 . 3898746 .
12. Wu. Hua-Jun. Landshammer. Alexandro. Stamenova. Elena K.. Bolondi. Adriano. Kretzmer. Helene. Meissner. Alexander. Michor. Franziska. 2021-08-12. Topological isolation of developmental regulators in mammalian genomes. Nature Communications. en. 12. 1. 4897. 10.1038/s41467-021-24951-7. 34385432 . 2041-1723. 8361032. 2021NatCo..12.4897W .
13. Mukherjee. Shreyasi. Chaturvedi. Praneet. Rankin. Scott A. Fish. Margaret B. Wlizla. Marcin. Paraiso. Kitt D. MacDonald. Melissa. Chen. Xiaoting. Weirauch. Matthew T. Blitz. Ira L. Cho. Ken WY. 2020-09-07. LaBonne. Carole. Morrisey. Edward E. Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network. eLife. 9. e58029. 10.7554/eLife.58029. 32894225 . 2050-084X. 7498262 . free .