Conserved microRNAs and Flipons Shape Gene Expression

An international team, including researchers of the HSE Faculty of Computer Science, has discovered a new mechanism of gene regulation in which microRNA assumes a central role. These non-coding molecules influence the DNA regions within genes that govern embryonic development. The study contributes to our understanding of the mechanisms underlying the diverse genetic programs found in complex multicellular organisms. The paper has been published in the International Journal of Molecular Sciences.

Living organisms experience continuous growth and development throughout their lifespan. Gene regulation plays a crucial role in governing this process. It controls the activation (expression) and deactivation (repression) of genes within the cell. These processes enable cells to adapt to fluctuations in the external environment while also regulating their growth, development, and functionality.

Traditionally, scientists have studied gene regulation in unicellular organisms (prokaryotes) by examining operons, which are functional groups of genes that encode proteins working simultaneously or sequentially. Operons are additionally regulated by proteins that interact with DNA.

In more sophisticated organisms like animals and plants (eukaryotes), gene regulation becomes considerably more complex, encompassing a multitude of mechanisms operating at various levels, ranging from interaction between transcription factors and DNA to regulation of protein synthesis and activity. MicroRNA molecules also play a pivotal role in the regulation of eukaryotic genes.

 

In their new paper, the scientists specifically investigate microRNAs characterised by a high degree of conservation, ie those that have maintained their function and nucleotide sequence across extensive evolutionary timeframes and among various species of organisms. The presence of conserved microRNAs across diverse species of multicellular animals (Metazoa) highlights their fundamental role in gene regulation processes and organismal development. This prompted their selection as the focus of the study.

The scientists have explored the interaction between microRNAs and flipons, which are DNA segments capable of modifying their structure and initiating or silencing gene activity. Flipons are found within gene promoters, specific DNA regions upstream of a gene's starting point which determine the precise timing and location of gene transcription initiation. The primary focus of the study was on the promoters of genes that play a pivotal role in embryonic development.

The study revealed that microRNAs are capable of regulating the genome by modulating the structure of flipons. Previously, it was believed that the two mechanisms, namely the regulation of genes through microRNAs and the alteration of flipon structures, operated independently of each other. However, it has been discovered that these mechanisms are in fact interconnected and can work synergistically to influence the processes of embryonic development. The interaction between these mechanisms enables a faster and more efficient adaptation to environmental changes, as microRNAs have the ability to evolve at a swifter pace compared to proteins.

The mechanism by which microRNAs and flipons operate at the embryonic level can be likened to a microcode, similar to a computer boot program that is initially installed to facilitate the subsequent download and installation of the complete operating system.

Maria Poptsova
Co-author of the paper, Head of the HSE International Laboratory of Bioinformatics

This discovery offers a fresh perspective on the processes of gene regulation in multicellular organisms and on the impact of such regulation on embryonic development. The findings obtained by the researchers exhibit a high statistical significance surpassing the threshold of five standard deviations, a criterion typically applied to discoveries in the physical sciences but uncommon in the biological sciences.

Further research may broaden our understanding of how the collaborative interaction between microRNAs and flipons contributes to precise and dynamic regulation of genes at various stages of embryonic development. This may lead to the discovery of new molecular mechanisms that underlie the diversity of genetic programs and their coordination within complex multicellular organisms.

Maria Poptsova
Co-author of the paper, Head of the HSE International Laboratory of Bioinformatics

IQ

July 10, 2023