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SET domain containing 2, histone lysine methyltransferase OKDB#: 5543
 Symbols: SETD2 Species: human
 Synonyms: LLS, HYPB, SET2, HIF-1, HIP-1, KMT3A, HBP231, HSPC069, p231HBP  Locus: 3p21.31 in Homo sapiens


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General Comment NCBI Summary: Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]
General function Enzyme , Epigenetic modifications
Comment
Cellular localization Nuclear
Comment
Ovarian function Oocyte maturation
Comment Histone methyltransferase SETD2 is required for meiotic maturation in mouse oocyte. Li C et al. (2018) SET-domain-containing 2 (SETD2), a member of the histone lysine methyltransferase family, has been reported to be involved in multiple biological processes. However, the function of SETD2 during oocyte maturation has not been addressed. In this study, we find that mouse oocytes are incapable of progressing through meiosis completely once SETD2 is specifically depleted. These oocytes present an abnormal spindle morphology and deficient chromosome movement, with disrupted kinetochore-microtubule attachments, consequently producing aneuploidy eggs. In line with this, the BubR1 signal is markedly elevated in metaphase kinetochores of oocytes with SETD2 depletion, indicative of the activation of spindle assembly checkpoint. In addition, we note that loss of SETD2 results in a drastic decrease in the trimethylation level of H3K36 in oocytes. Collectively, our data demonstrate that SETD2 is required for oocyte maturation and indicate a novel mechanism controlling the meiotic apparatus.//////////////////
Expression regulated by
Comment
Ovarian localization Oocyte
Comment Dynamic changes of SETD2, a histone H3K36 methyltransferase, in porcine oocytes, IVF and SCNT embryos. Diao YF et al. (2018) SETD2 (SET domain containing protein 2) acts as a histone H3 lysine 36 (H3K36)-specific methyltransferase and may play important roles in active gene transcription in human cells. However, its expression and role in porcine oocytes and preimplantation embryos are not well understood. Here, we used immunofluorescence and laser scanning confocal microscopy to examine SETD2 expression in porcine fetal fibroblasts, oocytes, and preimplantation embryos derived from in vitro fertilization (IVF), parthenogenetic activation (PA), and somatic cell nuclear transfer (SCNT). In porcine fetal fibroblasts, SETD2 expression was detected in interphase cells, but not in M (mitotic)-phase cells. The SETD2 signal was observed in non-surrounded nucleolus (NSN)-stage oocytes, but not in surrounded nucleolus (SN)-, metaphase I (MI)-, or metaphase II (MII)-stage oocytes. The SETD2 signal was detectable in sperm, and undetectable immediately after fertilization, detectable at the 2-cell stage, and peaked at the 4-cell stage of IVF embryos in which porcine embryonic genome is activated. Similar to the pattern found in IVF embryos, the SETD2 signal was absent from PA embryos at the 1-cell stage, but it was detected at the 2-cell stage and thereafter maintained to the blastocyst stage. Interestingly, unlike the IVF and PA embryos, the SETD2 signal was detected throughout the development of SCNT embryos, including at the 1-cell stage. These data suggest that SETD2 may be functional for embryonic gene transcription in porcine preimplantation embryos. It is further speculated that the aberrant expression of SETD2 at the 1-cell stage of porcine SCNT embryos may be a factor in the low efficiency of cloning in pig.//////////////////
Follicle stages
Comment
Phenotypes
Mutations 2 mutations

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development. Xu Q et al. (2019) The oocyte epigenome plays critical roles in mammalian gametogenesis and embryogenesis. Yet, how it is established remains elusive. Here, we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse oocyte epigenome. Deficiency in Setd2 leads to extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishing the correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories and aberrant acquisition of H3K4me3 at imprinting control regions instead of DNA methylation. Importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent one-cell arrest after fertilization. The preimplantation arrest is mainly due to a maternal cytosolic defect, since it can be largely rescued by normal oocyte cytosol. However, chromatin defects, including aberrant imprinting, persist in these embryos, leading to embryonic lethality after implantation. Thus, these data identify SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.//////////////////

Species: None
Mutation name:
type: null mutation
fertility: fertile
Comment: setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals. Liu DJ et al. (2020) Setd2 is the only enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Despite this widespread and conserved activity, Setd2 and H3K36me3 are dispensable for normal growth of yeast but are absolutely required for mammalian embryogenesis, such as oocyte maturation and embryonic vasculogenesis in mice, raising a question of how the functional requirements of Setd2 in specific developmental stages have emerged through evolution. Here, we explored this issue by studying the essentiality and function of Setd2 in zebrafish. Surprisingly, the setd2-null zebrafish are viable and fertile. They show Mendelian birth ratio and normal embryogenesis without vascular defect as seen in mice; however, they have a small body size phenotype attributed to insufficient energy metabolism and protein synthesis, which is reversable in a nutrition-dependent manner. Unlike the sterile Setd2-null mice, the setd2-null zebrafish can produce functional sperms and oocytes. Nonetheless, related to the requirement of maternal Setd2 for oocyte maturation in mice, the second generation of setd2-null zebrafish that carry no maternal setd2 show decreased survival rate and a developmental delay at maternal-to-zygotic transition. Taken together, these results indicate that, while the phenotypes of the setd2-null zebrafish and mice are apparently different, they are matched in parallel as the underlying mechanisms are evolutionarily conserved. Thus, the differential requirements of Setd2 may reflect distinct viability thresholds that associate with intrinsic and/or extrinsic stresses experienced by the organism through development, and these epigenetic regulatory mechanisms may serve as a reserved source supporting the evolution of life from simplicity to complexity.//////////////////

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created: Feb. 16, 2018, 1:45 p.m. by: system   email:
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last update: Oct. 29, 2020, 6:42 p.m. by: hsueh    email:



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