Temporal Control of the TGF-β Signaling Network by Mouse ESC MicroRNA Targets of Different Affinities

Timothy J Kelly; Anneke Brümmer; Nima Hooshdaran; Mito Tariveranmoshabad; Jesse R Zamudio

doi:10.1016/j.celrep.2019.10.109

Temporal Control of the TGF-β Signaling Network by Mouse ESC MicroRNA Targets of Different Affinities

Cell Rep. 2019 Nov 26;29(9):2702-2717.e7. doi: 10.1016/j.celrep.2019.10.109.

Authors

Timothy J Kelly¹, Anneke Brümmer², Nima Hooshdaran², Mito Tariveranmoshabad², Jesse R Zamudio³

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jesse.zamudio@ucla.edu.

Abstract

Although microRNAs (miRNAs) function in the control of embryonic stem cell (ESC) pluripotency, a systems-level understanding is still being developed. Through the analysis of progressive Argonaute (Ago)-miRNA depletion and rescue, including stable Ago knockout mouse ESCs, we uncover transforming growth factor beta (TGF-β) pathway activation as a direct and early response to ESC miRNA reduction. Mechanistically, we link the derepression of weaker miRNA targets, including TGF-β receptor 1 (Tgfbr1), to the sensitive TGF-β pathway activation. In contrast, stronger miRNA targets impart a more robust repression, which dampens concurrent transcriptional activation. We verify such dampened induction for TGF-β antagonist Lefty. We find that TGF-β pathway activation contributes to the G1 cell-cycle accumulation of miRNA-deficient ESCs. We propose that miRNA target affinity is a determinant of the temporal response to miRNA changes, which enables the coordination of gene network responses.

Keywords: Argonaute; RNAi; Smad; TGF-β; histone modifications; miRNA; post-transcriptional regulation; stem cells.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Differentiation
Humans
Mice
MicroRNAs / genetics*
Mouse Embryonic Stem Cells / metabolism*
Signal Transduction
Transforming Growth Factor beta / metabolism*

Substances

MicroRNAs
Transforming Growth Factor beta

Grants and funding

P01 CA042063/CA/NCI NIH HHS/United States