title: Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice.
abstract: We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5-14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level.
authors.affiliation: Medical Research Council (MRC) Harwell, Diabetes Group, Harwell Science and Innovation Campus, Oxfordshire, United Kingdom. m.goldsworthy@har.mrc.ac.uk
authors.forename: Michelle
authors.initials: M
authors.lastname: Goldsworthy
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Absalom
authors.forename: David
authors.initials: D
authors.lastname: Schröter
authors.forename: Helen C
authors.initials: HC
authors.lastname: Matthews
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.forename: Lee
authors.initials: L
authors.lastname: Moir
authors.forename: Anna
authors.initials: A
authors.lastname: Long
authors.forename: Christopher
authors.initials: C
authors.lastname: Church
authors.forename: Alison
authors.initials: A
authors.lastname: Hugill
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Rob
authors.initials: R
authors.lastname: Goldin
authors.forename: Mark
authors.initials: M
authors.lastname: Thursz
authors.forename: Florian
authors.initials: F
authors.lastname: Hollfelder
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005804:Genes, Lethal; D005951:Glucose Tolerance Test; D011495:Histone-Lysine N-Methyltransferase; D007333:Insulin Resistance / Q000235:genetics*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse