Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of kidneys from mice treated for eight weeks with the glucagon analogue, NNC9204-0043, compared to mice treated with PBS

ABSTRACT: Chronic glucagon receptor activation induced by a long-acting glucagon analogue causes thickening of the parietal layer of Bowman’s capsule, causes mesangial area expansion, and formation of albuminuria. To dissect the molecular mechanism underlying these effects, RNA sequencing of kidney biopsies from female mice treated for eight weeks with either the long-acting glucagon analogue, NNC9204-0043, or PBS were performed

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Christian Johansen

PROVIDER: E-MTAB-12520 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:During fasting, increases in circulating pancreatic glucagon maintain glucose balance by up-regulating hepatic gluconeogenesis. Triggering of the cAMP pathway stimulates the gluconeogenic program through the phosphorylation of CREB and via the de-phosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic genes by promoting epigenetic changes that facilitate assembly of the transcriptional machinery, although the nature of these modifications is unclear. Here we show that histone H3 acetylation at Lys 9 (H3K9Ac) is elevated over gluconeogenic genes during fasting and in diabetes, where it contributes to increases in hepatic glucose production. Following its dephosphorylation, CRTC2 promoted increases in H3K9Ac by mediating the recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat-containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. In turn, KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Breaking this cycle, by depletion of KAT2B or WDR5, decreased gluconeogenic gene expression. As administration of a small molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, our results demonstrate how this enzyme may be a useful target for diabetes treatment. A subset of cAMP responsive genes depend on specific recruitment of KAT2B (pcaf), which in concert with WDR5 acetylates H3K9. By selectively depleting hepatocytes for KAT2B or WDR5 prior to glucagon stimulation we explore, which genes rely on KAT2B and WDR5 activity. mKAT2B or mWDR5 were knocked down in primary mouse hepatocytes using adenoviral transduction with appropriate shRNAs. Control cells were transduced with a non-specific (NS) shRNA. 72 hours post transduction some cells were stimulated for 90 minutes with 100nM glucagon and others with PBS. Total RNA was purified and subjected to micro-RNA analysis. All samples are pools of RNA from three sepearate dishes. One replicate is included for most samples.

Dataset Information

RNA-seq of kidneys from mice treated for eight weeks with the glucagon analogue, NNC9204-0043, compared to mice treated with PBS

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