Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus

The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1.

Diagnosis of diabetes mellitus: case of different cutoff values: A data mining approach

Objective: An estimation of cut-off points for the diagnosis of diabetes mellitus (DM) based on individual risk factors. Methods: A subset of the 1991 Oman National Diabetes Survey is used, including all patients with a 2h post glucose load >= 200 mg/dl (278 subjects) and a control group of 286 subjects. All subjects previously diagnosed as diabetic and all subjects with missing data values were excluded. The data set was analyzed by use of the SPSS Clementine data mining system. Decision Tree Learners (C5 and CART) and a method for mining association rules (the GRI algorithm) are used. The fasting plasma glucose (FPG), age, sex, family history of diabetes and body mass index (BMI) are input risk factors (independent variables), while diabetes onset (the 2h post glucose load >= 200 mg/dl) is the output (dependent variable). All three techniques used were tested by use of crossvalidation (89.8%). Results: Rules produced for diabetes diagnosis are: A- GRI algorithm (1) FPG>=108.9 mg/dl, (2) FPG>=107.1 and age>39.5 years. B- CART decision trees: FPG >=110.7 mg/dl. C- The C5 decision tree learner: (1) FPG>=95.5 and 54, (2) FPG>=106 and 25.2 kg/m2. (3) FPG>=106 and =133 mg/dl. The three techniques produced rules which cover a significant number of cases (82%), with confidence between 74 and 100%. Conclusion: Our approach supports the suggestion that the present cut-off value of fasting plasma glucose (126 mg/dl) for the diagnosis of diabetes mellitus needs revision, and the individual risk factors such as age and BMI should be considered in defining the new cut-off value.