ABSTRACT
Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency.
ABSTRACT
OBJECTIVE: The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene. METHODS: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood. RESULTS: Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin. CONCLUSIONS: These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.
ABSTRACT
Parathyroid hormone (PTH) and the sympathetic tone promote Rankl expression in osteoblasts and osteoclast differentiation by enhancing cyclic adenosine monophosphate production through an unidentified transcription factor for PTH and through ATF4 for the sympathetic tone. How two extracellular cues using the same second messenger in the same cell elicit different transcriptional events is unknown. In this paper, we show that PTH favors Rankl expression by triggering the ubiquitination of HDAC4, a class II histone deacetylase, via Smurf2. HDAC4 degradation releases MEF2c, which transactivates the Rankl promoter. Conversely, sympathetic signaling in osteoblasts favors the accumulation of HDAC4 in the nucleus and its association with ATF4. In this context, HDAC4 increases Rankl expression. Because of its ability to differentially connect two extracellular cues to the genome of osteoblasts, HDAC4 is a critical regulator of osteoclast differentiation.
