{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRDM16 plays a critical role in hematopoietic regulation and leukemogenesis. In the context of gene therapy for immunodeficiencies, retroviral insertional activation involving PRDM16 has been shown to enhance long‐term myelopoiesis, while chromosomal rearrangements and fusion events—with partners such as RUNX1—are implicated in the pathogenesis of various acute leukemias. Moreover, aberrant expression of PRDM16 and its alternatively spliced isoform (MEL1S) has been linked to DNA hypomethylation changes and resistance to transforming growth factor–beta signaling, thereby contributing to malignant transformation in both pediatric and adult hematologic malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn adipose tissue, PRDM16 is recognized as a master regulator of brown fat determination and the browning process of white adipocytes. By interacting directly with transcriptional partners such as C/EBP‑β and MED1, it robustly induces a thermogenic gene program—including upregulation of UCP‑1—and facilitates cell fate switching from myoblast precursors to brown adipocytes. Moreover, post‐translational modifications including sumoylation further stabilize PRDM16, ensuring the sustained expression of key metabolic genes and thereby contributing to whole‐body energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular arena, PRDM16 is indispensable for maintaining myocardial integrity and proper cardiac metabolism. Genetic alterations and deletions affecting PRDM16 are linked to cardiomyopathies—such as left ventricular non‐compaction and hypertrophic cardiomyopathy—through mechanisms that include impaired mitochondrial function and aberrant gene regulation. Furthermore, common genetic variants in the PRDM16 locus have been correlated with electrocardiographic abnormalities, underscoring its role in cardiac electrophysiology and functional homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established roles in hematopoiesis, adipose tissue biology, and cardiac function, PRDM16 has emerged as a multifunctional regulator in several pathological contexts. Genetic association studies have implicated common variants of PRDM16 in migraine susceptibility, while epigenetic dysregulation of its promoter has been observed in tumors such as astrocytoma, prostate cancer, renal cell carcinoma, and lung cancer. In addition, polymorphisms in PRDM16 are associated with variations in lean body mass and may influence metastatic potential in invasive carcinomas, highlighting the diverse contributions of PRDM16 to disease pathogenesis and its promise as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ichiro Nishikata, Hidenori Sasaki, Mutsunori Iga, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-07-2482"}], "href": "https://doi.org/10.1182/blood-2003-07-2482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14656887"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14656887"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marion G Ott, Manfred Schmidt, Kerstin Schwarzwaelder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm1393"}], "href": "https://doi.org/10.1038/nm1393"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16582916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16582916"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Catherine Roche-Lestienne, Lauréline Deluche, Sélim Corm, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-07-102533"}], "href": "https://doi.org/10.1182/blood-2007-07-102533"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18202228"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18202228"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Francois P Duhoux, Geneviève Ameye, Carmen P Montano-Almendras, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2141.2011.08918.x"}], "href": "https://doi.org/10.1111/j.1365-2141.2011.08918.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22050763"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22050763"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "A Jo, S Mitani, N Shiba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2015.5"}], "href": "https://doi.org/10.1038/leu.2015.5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25567132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25567132"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Genki Yamato, Hiroki Yamaguchi, Hiroshi Handa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical features and prognostic impact of PRDM16 expression in adult acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.22483"}], "href": "https://doi.org/10.1002/gcc.22483"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28710806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28710806"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Gema Frühbeck, Pilar Sesma, María A Burrell "}, {"type": "b", "children": [{"type": "t", "text": "PRDM16: the interconvertible adipo-myocyte switch."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tcb.2009.01.007"}], "href": "https://doi.org/10.1016/j.tcb.2009.01.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19285866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19285866"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Harold S Sacks, John N Fain, Ben Holman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Uncoupling protein-1 and related messenger ribonucleic acids in human epicardial and other adipose tissues: epicardial fat functioning as brown fat."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2009-0571"}], "href": "https://doi.org/10.1210/jc.2009-0571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19567523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19567523"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shingo Kajimura, Patrick Seale, Kazuishi Kubota, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature08262"}], "href": "https://doi.org/10.1038/nature08262"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19641492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19641492"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Andrea Frontini, Alessandra Vitali, Jessica Perugini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbalip.2013.02.005"}], "href": "https://doi.org/10.1016/j.bbalip.2013.02.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23454374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23454374"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lei Huang, Dongning Pan, Qingbo Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor Hlx controls a systematic switch from white to brown fat through Prdm16-mediated co-activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-00098-2"}], "href": "https://doi.org/10.1038/s41467-017-00098-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28701693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28701693"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Qingbo Chen, Lei Huang, Dongning Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.02.057"}], "href": "https://doi.org/10.1016/j.celrep.2018.02.057"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29539416"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29539416"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Anne-Karin Arndt, Sebastian Schafer, Jorg-Detlef Drenckhahn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2013.05.015"}], "href": "https://doi.org/10.1016/j.ajhg.2013.05.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23768516"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23768516"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Kyung-Won Hong, Ji Eun Lim, Jong Wook Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu374"}], "href": "https://doi.org/10.1093/hmg/ddu374"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25035420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25035420"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Geoffroy Delplancq, Georges Tarris, Antonio Vitobello, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet C Semin Med Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.c.31766"}], "href": "https://doi.org/10.1002/ajmg.c.31766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31965688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31965688"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Dasan Mary Cibi, Kathleen Wung Bi-Lin, Shamini Guna Shekeran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.108288"}], "href": "https://doi.org/10.1016/j.celrep.2020.108288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33086060"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33086060"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Anne Francke Christensen, Ann-Louise Esserlind, Thomas Werge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The influence of genetic constitution on migraine drug responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cephalalgia (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0333102415610874"}], "href": "https://doi.org/10.1177/0333102415610874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26502740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26502740"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Qianqian Lei, Xiaoping Liu, Haijuan Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-101 reverses hypomethylation of the PRDM16 promoter to disrupt mitochondrial function in astrocytoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.6652"}], "href": "https://doi.org/10.18632/oncotarget.6652"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26701852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26701852"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Shaoxing Zhu, Yipeng Xu, Mei Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRDM16 is associated with evasion of apoptosis by prostatic cancer cells according to RNA interference screening."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2016.5605"}], "href": "https://doi.org/10.3892/mmr.2016.5605"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27511603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27511603"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Wenwen Lv, Xiao Yu, Wenxing Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low expression of LINC00982 and PRDM16 is associated with altered gene expression, damaged pathways and poor survival in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2018.6645"}], "href": "https://doi.org/10.3892/or.2018.6645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30132554"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30132554"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Isabel Tegeder, Katharina Thiel, Serap Erkek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurooncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11060-018-03018-6"}], "href": "https://doi.org/10.1007/s11060-018-03018-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30446899"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30446899"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Anirban Kundu, Hyeyoung Nam, Sandeep Shelar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRDM16 suppresses HIF-targeted gene expression in kidney cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20191005"}], "href": "https://doi.org/10.1084/jem.20191005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32251515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32251515"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Li Liu, Yuansi Chen, Jiaxin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The relationship between PRDM16 promoter methylation in abdominal subcutaneous and omental adipose tissue and obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Nutr (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clnu.2020.10.016"}], "href": "https://doi.org/10.1016/j.clnu.2020.10.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33127174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33127174"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "B K Mishra, S V Madhu, M Aslam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adipose tissue expression of UCP1 and PRDM16 genes and their association with postprandial triglyceride metabolism and glucose intolerance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes Res Clin Pract (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.diabres.2021.109115"}], "href": "https://doi.org/10.1016/j.diabres.2021.109115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34718051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34718051"}]}]}]}