Methyltransferase set7/9 maintains transcription and euchromatin structure at islet-enriched genes

Tye G. Deering, Takeshi Ogihara, Anthony P. Trace, Bernhard Maier, Raghu Mirmira

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

OBJECTIVE-The activation of β-cell genes, particularly of those encoding preproinsulin, requires an appropriate euchroma-tin(or "open")DNA template characterized by hypermethylation of Lys4 of histone H3. We hypothesized that this modification is maintained in islet β-cells by the action of the histone methyl-transferase Set7/9. RESEARCH DESIGN AND METHODS-To identify the role of Set7/9, we characterized its expression pattern and gene regulation and studied its function using RNA interference in both cell lines and primary mouse islets. RESULTS-Within the pancreas, Set7/9 protein shows striking specificity for islet cells, including α-and β-cells, as well as occasional cells within ducts. Consistent with these findings, the Set7/9 gene promoter contained an islet-specific enhancer located between-5,768 and-6,030 base pairs(relative to the transcriptional start site)that exhibited Pdx1-responsive activation in β-cells. To study Set7/9 function, we depleted insulinoma cells and primary mouse islets of Set7/9 protein using siRNA. Following siRNA treatment, we observed striking repression of genes involved in glucose-stimulated insulin secretion, including Ins1/2, Glut2, and MafA. These changes in transcription were accompanied by loss of dimethylated H3 Lys4 and RNA polymerase II recruitment, particularly at the Ins1/2 and Glut2 genes. Consistent with these data, depletion of Set7/9 in islets led to defects in glucose-stimulated Ca 2+ mobilization and insulin secretion. CONCLUSIONS We conclude that Set7/9 is required for normal β-cell function, likely through the maintenance of euchro-matin structure at genes necessary for glucose-stimulated insulin secretion.

Original languageEnglish
Pages (from-to)185-193
Number of pages9
JournalDiabetes
Volume58
Issue number1
DOIs
StatePublished - Jan 2009

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Euchromatin
Methyltransferases
Genes
Insulin
Islets of Langerhans
Glucose
Histones
Small Interfering RNA
Insulinoma
Tin
RNA Polymerase II
Gene Expression Regulation
Transferases
RNA Interference
Base Pairing
Transcriptional Activation
Pancreas
Proteins
Research Design
Maintenance

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Methyltransferase set7/9 maintains transcription and euchromatin structure at islet-enriched genes. / Deering, Tye G.; Ogihara, Takeshi; Trace, Anthony P.; Maier, Bernhard; Mirmira, Raghu.

In: Diabetes, Vol. 58, No. 1, 01.2009, p. 185-193.

Research output: Contribution to journalArticle

Deering, Tye G. ; Ogihara, Takeshi ; Trace, Anthony P. ; Maier, Bernhard ; Mirmira, Raghu. / Methyltransferase set7/9 maintains transcription and euchromatin structure at islet-enriched genes. In: Diabetes. 2009 ; Vol. 58, No. 1. pp. 185-193.
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