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FB2026_01
,
released March 12, 2026
The human SETD2 gene is the primary methyltransferase catalyzing H3K36 trimethylation (H3K36me3); methylation of this residue is associated with active chromatin. SETD2 also methylates non-histone substrates such as α-tubulin. There are a number of diseases associated with SETD2, including several neurodevelopmental syndromes (see MIM:612778) and a lengthy list of cancers. The Drosophila gene orthologous to SETD2 is Set2, for which a number of genetic reagents have been generated, including loss-of-function mutations, RNAi-targeting constructs, and overexpression constructs.
The human SETD2 gene has not been introduced into flies.
In Drosophila, animals homozygous for amorphic mutations of Dmel\Set2 typically die in late larval stages. A Drosophila model of SETD2-related diseases makes use of a specific variant ( SETD2:p.Glu902Gln , see the 'Disease-Implicated Variants' table below) that has been implicated in renal cell carcinoma as well as in a genetic neurodevelopmental syndrome, Luscan-Lumish syndrome (MIM:616831). The analogous mutational change has been introduced into the genomic Dmel\Set2 gene. Animals homozygous for this mutation are viable and fertile. Reduced levels of H3K36me3 histone methylation are detected in the female germline. In syncytial embryos, significant defects in spindle morphogenesis are also observed, consistent with the role of SETD2 in methylating α-tubulin during mitosis to regulate microtubule dynamics. Thus, this variant appears to act as a hypomorphic mutation that impacts multiple aspects of SETD2 function.
[updated May 2024 by FlyBase; FBrf0222196]
Mutations in SETD2 (both mono- and bi-allelic) have been found in many cancer types. The first cancer-associated SETD2 mutations were described in renal cell carcinoma and much of the subsequent studies have focused on the role of SETD2 mutations in that disease (Molenaar and van Leeuwen, 2022; pubmed:35661267).
SETD2 is implicated in several autosomal dominant disorders with neurodevelopmental and multi-systemic phenotypes. [from MIM:612778, 2024.05.13]
SETD2 is a tumor-suppressor gene: in cancers it is frequently inactivated (Molenaar and van Leeuwen, 2022; pubmed:35661267).
All three diseases associated with SETD2 exhibit autosomal dominant inheritance; see MIM:616831, MIM:620155, MIM:620157. [from MIM:612778, 2024.05.13]
SETD2 encodes a histone-lysine N-methyltransferase specific for lysine-36 of histone H3; methylation of this residue is associated with active chromatin. SETD2 also methylates non-histone substrates such as α-tubulin. [Gene Cards, SETD2, 240513]
Methylation of histone H3 Lys36 is associated with transcribed regions and functions in transcription fidelity, RNA splicing, and DNA repair. SETD2 is the primary methyltransferase catalyzing H3K36 trimethylation (H3K36me3) (summary by Xu et al., 2019, pubmed:31040401). [from MIM:612778, 2024.05.13]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human SETD2 (! Drosophila to 1 human).