Santiago Gerardo Medina-Muñoz1,2, Gopal Kushawah1, Luciana Andrea Castellano1, Michay Diez1, Michelle Lynn DeVore1, María José Blanco Salazar1,3, Ariel Alejandro Bazzini4,5. 1. Stowers Institute for Medical Research, 1000 E 50th St, Kansas City, MO, 64110, USA. 2. Present Address: National Laboratory of Genomics for Biodiversity (LANGEBIO), Unit of Advanced Genomics, 36824, Irapuato, Mexico. 3. Present Address: Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510, México City, Mexico. 4. Stowers Institute for Medical Research, 1000 E 50th St, Kansas City, MO, 64110, USA. arb@stowers.org. 5. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA. arb@stowers.org.
Abstract
BACKGROUND: The regulation of messenger RNA (mRNA) stability has a profound impact on gene expression dynamics during embryogenesis. For example, in animals, maternally deposited mRNAs are degraded after fertilization to enable new developmental trajectories. Regulatory sequences in 3' untranslated regions (3'UTRs) have long been considered the central determinants of mRNA stability. However, recent work indicates that the coding sequence also possesses regulatory information. Specifically, translation in cis impacts mRNA stability in a codon-dependent manner. However, the strength of this mechanism during embryogenesis, as well as its relationship with other known regulatory elements, such as microRNA, remains unclear. RESULTS: Here, we show that codon composition is a major predictor of mRNA stability in the early embryo. We show that this mechanism works in combination with other cis-regulatory elements to dictate mRNA stability in zebrafish and Xenopus embryos as well as in mouse and human cells. Furthermore, we show that microRNA targeting efficacy can be affected by substantial enrichment of optimal (stabilizing) or non-optimal (destabilizing) codons. Lastly, we find that one microRNA, miR-430, antagonizes the stabilizing effect of optimal codons during early embryogenesis in zebrafish. CONCLUSIONS: By integrating the contributions of different regulatory mechanisms, our work provides a framework for understanding how combinatorial control of mRNA stability shapes the gene expression landscape.
BACKGROUND: The regulation of messenger RNA (mRNA) stability has a profound impact on gene expression dynamics during embryogenesis. For example, in animals, maternally deposited mRNAs are degraded after fertilization to enable new developmental trajectories. Regulatory sequences in 3' untranslated regions (3'UTRs) have long been considered the central determinants of mRNA stability. However, recent work indicates that the coding sequence also possesses regulatory information. Specifically, translation in cis impacts mRNA stability in a codon-dependent manner. However, the strength of this mechanism during embryogenesis, as well as its relationship with other known regulatory elements, such as microRNA, remains unclear. RESULTS: Here, we show that codon composition is a major predictor of mRNA stability in the early embryo. We show that this mechanism works in combination with other cis-regulatory elements to dictate mRNA stability in zebrafish and Xenopus embryos as well as in mouse and human cells. Furthermore, we show that microRNA targeting efficacy can be affected by substantial enrichment of optimal (stabilizing) or non-optimal (destabilizing) codons. Lastly, we find that one microRNA, miR-430, antagonizes the stabilizing effect of optimal codons during early embryogenesis in zebrafish. CONCLUSIONS: By integrating the contributions of different regulatory mechanisms, our work provides a framework for understanding how combinatorial control of mRNA stability shapes the gene expression landscape.
Authors: John D Laver; Jimmy Ly; Allison K Winn; Angelo Karaiskakis; Sichun Lin; Kun Nie; Giulia Benic; Nima Jaberi-Lashkari; Wen Xi Cao; Alireza Khademi; J Timothy Westwood; Sachdev S Sidhu; Quaid Morris; Stephane Angers; Craig A Smibert; Howard D Lipshitz Journal: Cell Rep Date: 2020-03-10 Impact factor: 9.423
Authors: Sean E McGeary; Kathy S Lin; Charlie Y Shi; Thy M Pham; Namita Bisaria; Gina M Kelley; David P Bartel Journal: Science Date: 2019-12-05 Impact factor: 47.728