# DPPA3

## Overview
Developmental pluripotency associated 3 (DPPA3) is a gene that encodes the protein known as Stella or PGC7, which is integral to the regulation of pluripotency and epigenetic modifications in embryonic stem cells and germ cells. The DPPA3 protein is characterized by its interaction with the UHRF1 protein, specifically binding to its plant homeodomain (PHD) finger, which plays a crucial role in inhibiting chromatin localization and promoting passive DNA demethylation (Hata2022Structural). This protein is involved in maintaining DNA methylation patterns by displacing UHRF1 from chromatin, thereby preventing the recruitment of DNMT1 and facilitating a unique pathway of passive demethylation in mammals (Mulholland2020Recent). DPPA3 is essential for early embryonic development, safeguarding the genome from transposable elements, and maintaining pluripotency. Its clinical significance is underscored by its role in testicular germ cell tumors and its involvement in the reprogramming of somatic cells into induced pluripotent stem cells (Killian2016Imprints; Xu2015Dppa3).

## Structure
The human DPPA3 protein, also known as Stella or PGC7, exhibits distinct structural features that differentiate it from its mouse counterpart. The primary structure of human DPPA3 includes a conserved VRT sequence motif, which is crucial for its interaction with the UHRF1 PHD finger (Shiraishi2024Structure). The secondary structure of human DPPA3 is characterized by a single long α-helix following the VRT motif, which contrasts with the mouse DPPA3 that forms both short and long α-helices (Shiraishi2024Structure). This structural difference is attributed to a proline to lysine substitution at position 95 in human DPPA3 (Shiraishi2024Structure).

In terms of tertiary structure, the α-helix of human DPPA3 does not contact the UHRF1 PHD finger in the crystal structure, suggesting potential dimer formation or an artifact of crystal packing (Shiraishi2024Structure). The quaternary structure involves a 1:1 stoichiometry with the UHRF1 PHD finger, as supported by size-exclusion chromatography coupled with small-angle X-ray scattering (SEC-SAXS) data (Shiraishi2024Structure). The VRT motif plays a significant role in the interaction with the UHRF1 PHD finger, and mutations in this motif can affect binding affinity (Shiraishi2024Structure).

## Function
DPPA3, also known as Stella or PGC7, plays a crucial role in maintaining DNA methylation patterns in embryonic stem cells (ESCs) and is essential for safeguarding the naïve methylome. It acts downstream of TET1 and TET2 enzymes, which are involved in active DNA demethylation processes (Mulholland2020Recent). DPPA3 functions by displacing UHRF1 from chromatin, thereby preventing the recruitment of DNMT1 and the maintenance of DNA methylation in ESCs. This process is part of a unique pathway in mammals where TET proteins indirectly cause passive demethylation (Mulholland2020Recent). 

DPPA3 is involved in a recently evolved pathway that achieves global hypomethylation by coupling active and passive demethylation processes. TET enzymes are required for active demethylation, which is locus-specific and necessary for activating certain genes, including DPPA3. DPPA3 then drives large-scale passive demethylation by binding to and displacing UHRF1 from chromatin, inhibiting maintenance DNA methylation (Mulholland2020Recent). 

In the context of early embryonic development, DPPA3 is crucial for maintaining pluripotency and protecting the genome from transposable elements. It prevents global hypermethylation, particularly in transposable elements such as LINE and ERVs, and its absence leads to increased DNA methylation across various genomic features (Mulholland2020Recent).

## Clinical Significance
The DPPA3 gene, also known as STELLA or PGC7, plays a significant role in the epigenetic regulation of germ cells and embryonic stem cells. Alterations in DPPA3 expression or its interactions can have clinical implications, particularly in the context of testicular germ cell tumors (TGCTs). In TGCTs, DPPA3 is consistently hypomethylated, which is linked to its expression and the PGC-like origin of these tumors. This hypomethylation pattern is distinct and may contribute to the development and characteristics of TGCTs (Killian2016Imprints). The gene's role in maintaining imprint-erased states in TGCTs suggests a potential link to infertility and seminiferous competency (Killian2016Imprints).

DPPA3 is also involved in the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), where it enhances reprogramming efficiency and maintains the imprinting of the Dlk1-Dio3 cluster. Its absence can lead to reprogramming arrest and imprinting defects, indicating its critical role in genomic stability during reprogramming (Xu2015Dppa3). Additionally, DPPA3's interaction with chromatin and its role in DNA demethylation are crucial for normal development, and alterations in these processes could potentially impact fertility and embryogenesis (Toriyama2024DPPA3).

## Interactions
DPPA3, also known as Stella, interacts with the UHRF1 protein, specifically binding to its plant homeodomain (PHD) finger. This interaction inhibits UHRF1's chromatin localization and promotes passive DNA demethylation. DPPA3 achieves this by forming induced α-helices upon binding to UHRF1, which stabilizes the complex through multifaceted interactions. Mutations in DPPA3 that disrupt these interactions reduce its binding affinity to UHRF1 and impair its ability to inhibit UHRF1's chromatin recruitment and DNA methylation activity (Hata2022Structural).

The interaction between DPPA3 and UHRF1 is crucial for regulating UHRF1's E3-ligase activity, as DPPA3 represses this activity by preventing UHRF1 from ubiquitinating histone H3. This interaction is mediated by specific residues in DPPA3, such as those in the VRT cassette and α-helices, which are essential for binding to UHRF1 (Du2019Stella; Hata2022Structural).

In addition to its interaction with UHRF1, DPPA3 also interacts with ten-eleven translocation 3 (TET3) in somatic cells. However, this interaction does not depend on dimethylated histone H3 lysine 9 (H3K9me2), suggesting that other factors mediate the interaction between DPPA3 and TET3 (Wang2019Dimethylated).


## References


1. (Shiraishi2024Structure) Structure of human DPPA3 bound to the UHRF1 PHD finger reveals its functional and structural differences from mouse DPPA3. This article has 0 citations.

[2. (Du2019Stella) Wenlong Du, Qiang Dong, Zhuqiang Zhang, Baodong Liu, Ting Zhou, Rui-ming Xu, Hailin Wang, Bing Zhu, and Yingfeng Li. Stella protein facilitates dna demethylation by disrupting the chromatin association of the ring finger–type e3 ubiquitin ligase uhrf1. Journal of Biological Chemistry, 294(22):8907–8917, May 2019. URL: http://dx.doi.org/10.1074/jbc.ra119.008008, doi:10.1074/jbc.ra119.008008. This article has 33 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.ra119.008008)

[3. (Mulholland2020Recent) Christopher B. Mulholland, Atsuya Nishiyama, Joel Ryan, Ryohei Nakamura, Merve Yiğit, Ivo M. Glück, Carina Trummer, Weihua Qin, Michael D. Bartoschek, Franziska R. Traube, Edris Parsa, Enes Ugur, Miha Modic, Aishwarya Acharya, Paul Stolz, Christoph Ziegenhain, Michael Wierer, Wolfgang Enard, Thomas Carell, Don C. Lamb, Hiroyuki Takeda, Makoto Nakanishi, Sebastian Bultmann, and Heinrich Leonhardt. Recent evolution of a tet-controlled and dppa3/stella-driven pathway of passive dna demethylation in mammals. Nature Communications, November 2020. URL: http://dx.doi.org/10.1038/s41467-020-19603-1, doi:10.1038/s41467-020-19603-1. This article has 44 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-020-19603-1)

4. (Hata2022Structural) Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger. This article has 0 citations.

[5. (Wang2019Dimethylated) Qian-Qian Wang, Yu-Mei Zhang, Xia Zhong, Jian-Wei Li, Xiao-Rong An, and Jian Hou. Dimethylated histone h3 lysine 9 is dispensable for the interaction between developmental pluripotency-associated protein 3 (dppa3) and ten-eleven translocation 3 (tet3) in somatic cells. Reproduction, Fertility and Development, 31(2):347, 2019. URL: http://dx.doi.org/10.1071/rd18062, doi:10.1071/rd18062. This article has 3 citations.](https://doi.org/10.1071/rd18062)

[6. (Killian2016Imprints) J. Keith Killian, Lambert C.J. Dorssers, Britton Trabert, Ad J.M. Gillis, Michael B. Cook, Yonghong Wang, Joshua J. Waterfall, Holly Stevenson, William I. Smith, Natalia Noyes, Parvathy Retnakumar, J. Hans Stoop, J. Wolter Oosterhuis, Paul S. Meltzer, Katherine A. McGlynn, and Leendert H.J. Looijenga. Imprints and dppa3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors. Genome Research, 26(11):1490–1504, October 2016. URL: http://dx.doi.org/10.1101/gr.201293.115, doi:10.1101/gr.201293.115. This article has 44 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1101/gr.201293.115)

[7. (Toriyama2024DPPA3) Keisuke Toriyama, Wan Kin Au Yeung, Azusa Inoue, Kazuki Kurimoto, Yukihiro Yabuta, Mitinori Saitou, Toshinobu Nakamura, Toru Nakano, and Hiroyuki Sasaki. Dppa3 facilitates genome-wide dna demethylation in mouse primordial germ cells. BMC Genomics, April 2024. URL: http://dx.doi.org/10.1186/s12864-024-10192-7, doi:10.1186/s12864-024-10192-7. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12864-024-10192-7)

[8. (Xu2015Dppa3) Xingbo Xu, Lukasz Smorag, Toshinobu Nakamura, Tohru Kimura, Ralf Dressel, Antje Fitzner, Xiaoying Tan, Matthias Linke, Ulrich Zechner, Wolfgang Engel, and D. V. Krishna Pantakani. Dppa3 expression is critical for generation of fully reprogrammed ips cells and maintenance of dlk1-dio3 imprinting. Nature Communications, January 2015. URL: http://dx.doi.org/10.1038/ncomms7008, doi:10.1038/ncomms7008. This article has 46 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms7008)