{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2DNL, also known as Rae28, is an essential component of the Polycomb group (PcG) complex 1 that safeguards established transcriptional states by modulating chromatin architecture. Its proper function is critical in hematopoietic stem cells (HSCs), where deficiency leads to a dramatic reduction in both the number of HSCs and their self‐renewal capacity, as well as impaired colony formation. Moreover, Rae28 plays a key role in facilitating ubiquitin–proteasome–mediated degradation of specific cell cycle regulators—such as Geminin—thereby promoting cell cycle progression and genomic stability in the HSC compartment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, UBE2DNL contributes to the assembly and function of higher-order PcG complexes through defined protein–protein interactions. Studies of SAM domain polymerization indicate that Rae28, like other polyhomeotic orthologues, cooperates with proteins such as Ph and Scm to form flexible and extended repression assemblies. These multimeric structures appear to coordinate the long-range repression of developmental regulators and are part of a broader network that includes redundancies and dose-dependent interactions required for maintaining positional information during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in stem cell regulation, UBE2DNL is also a pivotal factor in cardiac morphogenesis. In the developing heart, Rae28 is required not for the initial activation but for the sustained expression of the cardiac selector gene Nkx2.5/CSX—necessary for proper heart formation. Genetic complementation experiments demonstrate that only ubiquitous (non–cardiomyocyte–restricted) expression of UBE2DNL can rescue the cardiac defects seen in its deficiency, while its inappropriate overexpression in cardiomyocytes can induce dilated cardiomyopathy, underscoring a critical dosage and non–cell autonomous mechanism during organogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hideaki Ohta, Akihisa Sawada, Ji Yoo Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20011911"}], "href": "https://doi.org/10.1084/jem.20011911"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11901201"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11901201"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ji Yoo Kim, Akihisa Sawada, Sadao Tokimasa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective long-term repopulating ability in hematopoietic stem cells lacking the Polycomb-group gene rae28."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Haematol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0609.2004.00268.x"}], "href": "https://doi.org/10.1111/j.1600-0609.2004.00268.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15245505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15245505"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Motoaki Ohtsubo, Shin'ichiro Yasunaga, Yoshinori Ohno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0800672105"}], "href": "https://doi.org/10.1073/pnas.0800672105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18650381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18650381"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hideyuki Koga, Yoshikazu Kaji, Kiyomasa Nishii, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of Polycomb-group gene rae28 in cardiomyocytes does not complement abnormal cardiac morphogenesis in mice lacking rae28 but causes dilated cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/labinvest.3780432"}], "href": "https://doi.org/10.1038/labinvest.3780432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11950896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11950896"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Chongwoo A Kim, Michael R Sawaya, Duilio Cascio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural organization of a Sex-comb-on-midleg/polyhomeotic copolymer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M503055200"}], "href": "https://doi.org/10.1074/jbc.M503055200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15905166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15905166"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kyo-Ichi Isono, Yu-Ichi Fujimura, Jun Shinga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.15.6694-6706.2005"}], "href": "https://doi.org/10.1128/MCB.25.15.6694-6706.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16024804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16024804"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Manabu Shirai, Tomoaki Osugi, Hideyuki Koga, et al. 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