JMJD1C

Official Full Name

jumonji domain containing 1C

Organism

Homo sapiens

GeneID

221037

Background

The protein encoded by this gene interacts with thyroid hormone receptors and contains a jumonji domain. It is a candidate histone demethylase and is thought to be a coactivator for key transcription factors. It plays a role in the DNA-damage response pathway by demethylating the mediator of DNA damage checkpoint 1 (MDC1) protein, and is required for the survival of acute myeloid leukemia. Mutations in this gene are associated with Rett syndrome and intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Synonyms

KDM3C; TRIP8; TRIP-8;

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Detailed Information

Recent Research

JMJD1C is a H3K9 demethylase, (also named TRIP8 or KDM3C), which has been shown to keep the balance of histone methylation status through interaction with histone methyltransferases and WHISTLE for transcriptional regulation. JMJD1C, directly interacts with the regulatory circuitry formed by OCT4, miR-302, and NR2F2 controls. JMJD1C is a part of the regulatory circuit that prevents human embryonic stem cells (hESCs) from neural differentiation by demethylating H3K9 at the locus of a pluripotency-associated microRNA, the miR-302/367 gene cluster. Some reports show that hESCs with stable knockdown of JMJD1C remain pluripotent while having reduced miR-302 expression, decreased BMP signaling, and enhanced TGF signaling. JMJD1C was reported to bind to the miR-302 promoter and reduces H3K9 methylation. Expression of a histone demethylase, JMJD1C is highly correlated to the pluripotent state. JMJD1C is highly expressed in hESCs and declines during hESC differentiation in response to either activation of BMP signaling or inhibition of TGF and/or FGF signaling. Furthermore, the JMJD1C promoter contains a putative OCT-binding site, suggesting that JMJD1C may play a role in the regulatory circuit of pluripotency as a downstream target gene of OCT4. Therefore, JMJD1C also represses neural differentiation by modulating TGF and BMP signaling.

Jmjd1C is one of the Jmjd1 family genes that encode putative demethylases against histone H3K9 and non-histone proteins and has been proven to play an important role in mouse spermatogenesis. Jmjd1C gene-trap homozygous testes exhibited malformations in post meiotic processes and a deficiency in the long-term maintenance of undifferentiated spermatogonia. JMJD1C may participate in the maintenance of spermatogonial stem cell self-renewal by up-regulating Oct4 expression. JMJD1C contributed to the long-term maintenance of male germ cells. JMJD1C has multiple functions during spermatogenesis through interactions with different partners during the spermatogenic stages. JMJD1C is unlikely to have a direct effect on the transcriptional regulation of these germ cell-specific genes. Jmjd1C has an indirect function in the regulation of histone H4K16 hyper-acetylation that leads to histone-protamine remodeling during sperm formation, although the action mechanism remains undefined. Oct4 expression under the control of JMJD1C is closely related to the maintenance of SSC self-renewal and/or survival similar to the pluripotency of ES cells. Therefore, Jmjd1C had multiple functions in chromatin remodeling during spermiogenesis and the maintenance of spermatogonial stem cells that were accompanied by multiple partner proteins.

Depletion of Jmjd1c impairs growth and colony formation of mouse MLL-AF9 cells in vitro, as well as establishment of leukemia after transplantation. Depletion of JMJD1C impairs expansion and colony formation of human leukemic cell lines, with the strongest effect observed in the MLL-rearranged ALL cell line, SEM. In both mouse and human leukemic cells, the growth defect upon JMJD1C depletion appears to be primarily due to increased apoptosis, which implicates JMJD1C as a potential therapeutic target in leukemia. Leukemic cells are more sensitive to Jmjd1c depletion than normal BM cells. Mouse LSK cells exhibit only mild phenotype after Jmjd1c knock-down. Jmjd1c depletion does not have a major impact on hematopoietic progenitors, at Jmjd1c knock-down efficiency similar to MLL-AF9 transformed hematopoietic cells. JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity.

References:

Ryusuke N, et al. JMJD1C Exhibits Multiple Functions in Epigenetic Regulation during Spermatogenesis. Plos One, 2016, 11(9):e0163466.
Sáez M A, et al. Mutations in JMJD1C are involved in Rett syndrome and intellectual disability. Genetics in Medicine, 2016, 18(4):378-385.
Sroczynska P, et al. shRNA screening identifies JMJD1C as being required for leukemia maintenance.[J]. Blood, 2014, 123(12):1870-82.
Wang J, et al. Epigenetic Regulation of miR-302 by JMJD1C Inhibits Neural Differentiation of Human Embryonic Stem Cells. Journal of Biological Chemistry, 2014, 289(4):2384-95.

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