The GATA Factor elt-1 Regulates C. elegans Developmental Timing by Promoting Expression of the let-7 Family MicroRNAs

Max L Cohen,Min Han,Seong Heon Kim,Kiyokazu Morita,Sunhong Kim,Susan E Mango

doi:10.1371/journal.pgen.1005099

Abstract

Postembryonic development in Caenorhabditis elegans is a powerful model for the study of the temporal regulation of development and for the roles of microRNAs in controlling gene expression. Stable switch-like changes in gene expression occur during development as stage-specific microRNAs are expressed and subsequently down-regulate other stage-specific factors, driving developmental progression. Key genes in this regulatory network are phylogenetically conserved and include the post-transcriptional microRNA repressor LIN-28; the nuclear hormone receptor DAF-12; and the microRNAs LIN-4, LET-7, and the three LET-7 family miRNAs (miR-48, miR-84, and miR-241). DAF-12 is known to regulate transcription of miR-48, miR-84 and miR-241, but its contribution is insufficient to account for all of the transcriptional regulation implied by the mutant phenotypes. In this work, the GATA-family transcription factor ELT-1 is identified from a genetic enhancer screen as a regulator of developmental timing in parallel to DAF-12, and is shown to do so by promoting the expression of the LET-7, miR-48, miR-84, and miR-241 microRNAs. The role of ELT-1 in developmental timing is shown to be separate from its role in cell-fate maintenance during post-embryonic development. In addition, analysis of Chromatin Immnoprecipitation (ChIP) data from the modENCODE project and this work suggest that the contribution of ELT-1 to the control of let-7 family microRNA expression is likely through direct transcription regulation.

Highlights

Extensive study of postembryonic development in the nematode Caenorhabditis elegans has advanced our understanding of the temporal regulation of development and the roles of microRNAs in controlling gene expression [1,2,3,4,5]
The presence of ELT-1 in vivo binding near microRNA coding DNA sequences suggests that its contribution to the regulation of microRNA expression is likely through direct regulation of transcription
These results indicate that elt-1/GATA has an important role in regulating developmental timing in parallel to daf-12. daf-12 is known to regulate developmental timing by promoting the expression of the three LET-7 family miRNAs [27,28], suggesting that elt-1 may regulate developmental timing by acting either in parallel to or upstream of the miRNAs

Summary

Introduction

Extensive study of postembryonic development in the nematode Caenorhabditis elegans has advanced our understanding of the temporal regulation of development and the roles of microRNAs (miRNAs) in controlling gene expression [1,2,3,4,5]. Dafachronic acid steroid hormones are synthesized by C. elegans in response to favorable growth conditions [24] They stimulate the nuclear hormone receptor (NHR) DAF-12, the vitamin D NHR ortholog, to promote progression from the 2nd larval stage (L2) to the 3rd larval stage (L3) [24,25,26] by, in part, initiating expression of the LET7 family of miRNAs, miR-48, miR-84, and miR-241, during or near the L2-to-L3 molt [27,28]. The presence of other regulatory factors that act on the transcription of these miRs is implied, and the identification of these factors would significantly advance our understanding of developmental timing regulation as well of miRNA function in general

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Conclusion