Work

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

Year: 2019

Type: article

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.

Source: Cell Reports

DOI: 10.1016/j.celrep.2019.10.109

Authors: Timothy J. Kelly, Anneke Brümmer, Nima Hooshdaran, Mito Tariveranmoshabad, Jesse R. Zamudio

Institutions: Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, University of California, Los Angeles, Broad Center, UCLA Jonsson Comprehensive Cancer Center

Language: English

Topic: MicroRNA in disease regulation

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,200