Extensive changes in histone methylation with age are associated with downregulation of growth-promoting genes during juvenile growth deceleration

Presentation Number: SAT-394
Date of Presentation: June 15th, 2013

Julian Lui*1 and Jeffrey Baron2
1NICHD, Bethesda, MD, 2NIH, Bethesda, MD

Abstract

During early postnatal life, extensive changes in gene expression occur in major organs, contributing to the decline in cell proliferation, and thus to body growth deceleration. In rodents, this juvenile genetic program comprises hundreds of growth-promoting genes, including Igf2, Ezh2, and Mycn, that become downregulated with age concurrently in liver, kidney, lung, and heart. To investigate epigenetic changes that might be orchestrating these changes in gene expression, we performed chromatin immunoprecipitation-promoter tiling array (ChIP-on-chip, Affymetrix GeneChip promoter array 1.0R, > 28,000 mouse promoter regions) to assess temporal changes in histone H3K4 and H3K27 trimethylation (me3) at promoter regions throughout the genome in kidney and lung, comparing 1- to 4-wk-old C57BL/6 mice. We then correlated these changes in histone methylation with changes in mRNA expression assessed by microarray (Affymetrix Mouse Genome Array 430 2.0, > 39,000 mouse transcripts). From 1 to 4-wk, changes in gene expression correlated positively with changes in H3K4me3 (P<0.0001) and correlated negatively with H3K27me3 (P<0.0001), in both kidney and lung. Consistently, age-downregulated genes (≥1.5-fold, FDR<0.01) were significantly enriched with genes showing decreased promoter H3K4me3 and increased H3K27me3 (P<0.0001), while age-upregulated genes (≥1.5-fold, FDR<0.01) were significantly enriched for increased H3K4me3 and decreased H3K27me3 (P<0.0001). We next compared the two organs and found that the number of genes with concordant changes in histone methylation in kidney and lung was much greater than would be expected by chance. For example, of 2,500 genes that showed decreased H3K4me3 in kidney, 816 genes also showed decreased H3K4 in lung (P<0.001). Interestingly, gene ontology analysis showed that the genes with concordant decreases in H3K4me3 with age are strongly implicated in cell cycle and cell proliferation functions, suggesting that the decline of this histone mark is associated with the concordant downregulation of many growth-regulating genes with age.

Taken together, our combined ChIP-on-chip and expression array analysis in mouse suggests that, during early postnatal life, extensive genome-wide changes in H3K4me3 and H3K27me3 with age may help orchestrate the changes in gene expression occurring concordantly in multiple organs. In particular, the loss of H3K4me3 at the promoter regions of many growth-promoting genes may contribute to their downregulation with age, thus driving juvenile growth deceleration.

 

Nothing to Disclose: JL, JB