Glucose Regulates Insulin Gene Transcription by Hyperacetylation of Histone H4

Abstract

Induction of insulin gene expression in response to high blood glucose levels is essential for maintaining glucose homeostasis. Although several transcription factors including Beta-2, Ribe3b1, and Pdx-1 have been shown to play a role in glucose stimulation of insulin gene expression, the exact molecular mechanism(s) by which this regulation occurs is unknown. Previous data demonstrate that the transcription factors Beta-2/NeuroD1 and Pdx-1, which are involved in glucose-stimulated insulin gene expression, interact with the histone acetylase p300, suggesting a role for histone acetylation in glucose regulation of the insulin gene expression. We report that exposure of mouse insulinoma 6 cells to high concentrations of glucose results in hyperacetylation of histone H4 at the insulin gene promoter, which correlates with the increased level of insulin gene transcription. In addition, we demonstrate that hyperacetylation of histone H4 in response to high concentrations of glucose also occurs at the glucose transporter-2 gene promoter. Using histone deacetylase inhibitors, we show that increases in histone H4 acetylation cause stimulation of insulin gene transcription even in the absence of high concentrations of glucose. Furthermore, we show that fibroblasts, which lack insulin gene expression, also lack histone acetylation at the insulin gene promoter. In summary, our data support the idea that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter.

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…This result may be secondary to the recruitment of the histone methyltransferase Set7/9 by Pdx1 [147]. Similarly, the glucose-stimulated increase in histone H4 acetylation (another marker of active, open chromatin) at the insulin gene in both cell lines and islets by Pdx1 is consistent with its recruitment of the histone acetyltransferase p300 [145,153,154]. These results suggest that an important component of gene activation by the Pdx1 protein complex may be its direct alteration of chromatin to a more open state, thereby permitting enhanced accessibility to other transcription factors and the basal transcriptional machinery.…”

“…Apart from interaction with transcription factors, Pdx1 also appears to recruit transcriptional co-activators (proteins that bridge Pdx1 to the basal transcriptional machinery), including CBP/ p300 [68,113,141,145,146], Set7/9 [147], Bridge-1 [148], PCIF1 [149], and histone deacetylases (HDACs) [150]. Once recruited, cofactors are believed to serve as a physical or functional "bridge" that allows Pdx1 to communicate with components of the basal transcriptional machinery.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Thus, glucose modulates the transcription of the insulin gene by hyperacetylation of histone H4 (Mosley and Ozcan, 2003). In fact, the histone acetyltransferase p300 is recruited to the insulin promoter only at high concentrations of glucose via its interaction with the beta-cell-specific transcription factor Pdx-1 (Mosley et al, 2004).…”

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

“…These events appear to be necessary for preproinsulin transcription induced by glucose (96-100). Conversely, at low glucose levels where insulin production is shut off, the acetylation of histone H4 at the insulin promoter is abolished, correlating with recruitment of HDAC1 and -2 to the in- sulin promoter by Pdx1 (97,101). NeuroD1 also interacts with p300 and is acetylated by the p300-associated factor (PCAF).…”

“…The HDACi TSA and NaB increase histone H4 acetylation and enhance insulin expression at low glucose levels (3 mmol/L), supporting a repressive role of HDACs on preproinsulin transcription (97). Of note, TSA and NaB did not potentiate acetylation of H4 after exposure to high concentrations of glucose (30 mmol/L) (97). A stimulatory effect of VPA on insulin release has also been reported in human islets incubated in low glucose concentrations (2.8 mmol/L) (107).…”