Gadd45a opens up the promoter regions of miR-295 facilitating pluripotency induction

Linpeng Li,Bochao Ma,Duanqing Pei,Qi Long,Keshi Chen,Danyun Zhao,Xingguo Liu,Yi Wu

doi:10.1038/cddis.2017.497

Abstract

MicroRNAs (miRNAs) play crucial roles in the establishment of pluripotent state by controlling pluripotent network. However, the molecular mechanisms controlling miRNAs during somatic cell reprogramming remain obscure. In this study, we show Gadd45a (growth arrest and DNA-damage-inducible protein 45a) enhances reprogramming by activating miR-295. Furthermore, we show that Gadd45a binds the promoter regions of miR-295. Nuclease accessibility assay indicates that Gadd45a opens the promoter regions of miR-295. Levels of H3K9Ac and H3K27Ac on the promoter regions of miR-295 were also increased. In conclusion, our results indicate that Gadd45a relaxes the promoter regions of miR-295 and promotes the expression of miR-295 during reprogramming, implying a concise mechanism of Gadd45a and miR-290 cluster cooperation in cell-fate determination.

Highlights

RNAs that regulate gene expression and control many physiological processes including development, homeostasis and metabolism.[1,2] Aberrant miRNA expression is involved in cancer and many other diseases.[3,4] Recent studies have revealed that miRNAs play critical roles in pluripotency maintenance and somatic cell reprogramming.[5,6]
MiR-34 is a target of P53, a known repressor of reprogramming.[17,19,20] miR-21 and miR-29a are abundantly expressed in mouse embryonic fibroblasts (MEFs) and depletion of each results in enhanced reprogramming efficiency.[18,21]
We reported that Gadd45a is a heterochromatin relaxer that could enhance somatic cell reprogramming efficiency.[26]

Summary

Introduction

RNAs that regulate gene expression and control many physiological processes including development, homeostasis and metabolism.[1,2] Aberrant miRNA expression is involved in cancer and many other diseases.[3,4] Recent studies have revealed that miRNAs play critical roles in pluripotency maintenance and somatic cell reprogramming.[5,6]. Several miRNAs including miR-291-3p, miR-294 and miR-295 form the miR-290 cluster and belong to the embryonic stem cell-specific cell cycle regulating miRNAs7 that enhance the generation of mouse induced pluripotent stem cells (iPSCs) using Sox[2], Klf[4] and Oct[4] (SKO).[8] The miR-290 cluster is involved in the epigenetic control of gene expression and is suggested to promote the G1/S transition to accelerate cell proliferation.[7,9] Other miRNAs, such as the miR-302 and miR-200 clusters, have been shown to enhance reprogramming through promoting the mesenchymal-to-epithelial transition,[10,11,12] an early event in the reprogramming of fibroblasts.[13,14]. 45a) is a potential RNA-binding protein involved in many cellular processes including cell cycle, senescence, tumor progression, DNA repair and active DNA demethylation.[22,23,24]

Methods

Results

Conclusion