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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Innate Control of Early Embryonic Development

Alternative title: Medfødt kontroll av tidlig embryonisk utvikling

Awarded: NOK 12.5 mill.

Complex organisms, built of trillions of different cells, arise from a single cell - zygote. The zygote contains parental instruction of the development. This instruction is written in multiple layers of DNA, RNA and proteins, connected in a regulatory network. One of the most fundamental questions in biology is how this parental information is executed. The InnControl project focuses on regulation of early development in two model fish: zebrafish and medaka. We employ high-throughput methods to map dynamics of global regulatory transcriptome and proteome, as well as epigenetic modifications of genome and transcriptome in the earliest phases of embryonic life. To elucidate regulatory mechanisms, we generate models with impaired essential regulatory elements. We evaluate the effects of environmental modulation on parental epigenetic instruction. So far, we have produced a baseline information on dynamics of early developmental proteome, elucidated functionality of several regulatory RNAs of maternal origin in early embryo formation, developed a set of bioinformatics tools to investigate small RNAs, produced a map of ribosomal RNA modifications in embryonic development of zebrafish and medaka, produced direct RNA sequencing of developmental transcriptomes, and mapped m6A RNAS modifications in developmental transcriptomes using SAC-seq method. Currently, we analyse data on the effect of environmental stressors on parental epigenetic information and on regulatory transcriptomes, and analyse the data on transcriptional permissiveness of early embryonic genomes using KAS-seq method.

Regulation of development from the onset of a multicellular organism's formation is of fundamental scientific importance, because it sheds light on one of the principal mechanisms of life. The current understanding of the process is that maternally provided factors drive the development, while the zygotic genome is initially inactive in regulatory functions. The InnControl project challenges this long-standing dogma. We hypothesize that two additional regulatory layers exist before the maternal-to-zygotic transition, a recognized regulatory switch point. The project brings together internationally renowned academic experts in transcriptomics, proteomics, functional genomics, RNA biology, fish reproductive and developmental biology, epigenomics, and notably, team members being in forefront of science and method development in epitranscriptomics. Teleost fish, zebrafish and medaka, will be model organisms. We will combine high-throughput analyses of transcriptome, epitranscriptome, epigenome, and proteome with functional genomics. We will generate models with impaired essential elements of transcription, miRNA biogenesis machinery, and RNA-guided repression machinery, on different levels of interference: genetic loss-of-function (knockout), transcript level manipulation (knockdown or mimics) and protein inhibition. We will characterize early developmental epitranscriptome and elucidate its role in zygote formation. We will experimentally test the effect of environmental modulation on parental epigenetic instruction and analyse DNA and RNA methylomes. Finally, we will determine long-term effect of environmental modulation on epigenetic inheritance. This project aims to contribute substantially to the understanding of regulation of Metazoan development, with direct impact on medicine, ecology and biotechnology. Also, the project will develop innovative high-throughput methods within genomics.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol