Broad shifts in gene expression during early postnatal life are associated with shifts in histone methylation patterns.

Julian C Lui,Jeffrey Baron,Weiping Chen,Crystal S F Cheung,Michael Schubert

doi:10.1371/journal.pone.0086957

Abstract

During early postnatal life, extensive changes in gene expression occur concomitantly in multiple major organs, indicating the existence of a common core developmental genetic program. This program includes hundreds of growth-promoting genes that are downregulated with age in liver, kidney, lung, and heart, and there is evidence that this component of the program drives the widespread decline in cell proliferation that occurs in juvenile life, as organs approach adult sizes. To investigate epigenetic changes that might orchestrate this program, we performed chromatin immunoprecipitation-promoter tiling array 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 mice. We found extensive genome-wide shifts in H3K4me3 and H3K27me3 occurring with age in both kidney and lung. The number of genes with concordant changes in the two organs was far greater than expected by chance. Temporal changes in H3K4me3 showed a strong, positive association with changes in gene expression, assessed by microarray, whereas changes in H3K27me3 showed a negative association. Gene ontology analysis indicated that shifts in specific histone methylation marks were associated with specific developmental functions. Of particular interest, genes with decreases in H3K4me3 with age in both organs were strongly implicated in cell cycle and cell proliferation functions. Taken together, the findings suggest that the common core developmental program of gene expression which occurs in multiple organs during juvenile life is associated with a common core developmental program of histone methylation. In particular, declining H3K4me3 is strongly associated with gene downregulation and occurs in the promoter regions of many growth-regulating genes, suggesting that this change in histone methylation may contribute to the component of the genetic program that drives juvenile body growth deceleration.

Highlights

Posttranslational modifications of histone protein are thought to be important epigenetic marks closely associated with transcriptional regulation [1]
We performed chromatin immunoprecipitation (ChIP) with genomic DNA isolated from normal mouse kidney and lung at 1and 4-wk of age using antibodies that recognize specific histone modifications H3K4me3 or H3K27me3
Tiling array analysis of 1-wk old kidney and lung suggested that the distribution of H3K4me3 and H3K27me3 marks across the genome is very similar between the two organs (Fig. 1A)

Summary

Introduction

Posttranslational modifications of histone protein are thought to be important epigenetic marks closely associated with transcriptional regulation [1]. Methylation of H3K4 is associated with transcriptional activation, and methylation of H3K27 with transcriptional repression [1,2,3,4]. Both histone methylation marks are proposed to be instrumental in gene regulation during mammalian development [4,5,6]. In mouse embryonic stem cells (ESCs), genes involved in the maintenance of pluripotency like Sox are actively transcribed, and its promoter is marked strongly by trimethylation of H3K4 (H3K4me3) [7]. The combination of ‘‘activation’’ and ‘‘repression’’ histone mark is usually associated with temporary silencing of the gene locus, with the gene remaining ‘‘poised’’ for expression once the repressive H3K27me mark is removed [7,8,9]

Methods

Results

Conclusion