Genome-Wide Atlas of Promoter Expression Reveals Contribution of Transcribed Regulatory Elements to Genetic Control of Disuse-Mediated Atrophy of Skeletal Muscle.

Sergey S Pintus,Guzel R Gazizova,Islam Nigmetzyanov,Elena Shagimardanova,Daniil Popov,Pavel Makhnovskii,Ivan Yevshin,Oksana Tyapkina,Oleg Gusev,Fedor A Kolpakov,Leniz Nurullin,Ilya R Akberdin,Ruslan Devyatiyarov

doi:10.3390/biology10060557

Abstract

Simple SummaryThe genetic process underlying the control of skeletal muscle homeostasis is a key factor in methods that develop technologies to prevent age and immobility-driven atrophy. In the current paper, using advanced methods for the whole-genome profiling of transcription starting sites in fast and slow muscle in rats, we developed an integrative database of transcribed regulatory elements. Employing methods of comparative transcriptomics, we demonstrate that cis-regulatory elements are actively involved in the control of atrophy and recovery, and that the differential use of promoters and enhancers is the one of the key mechanisms that distinguishes between specific processes in slow and fast skeletal muscles.The prevention of muscle atrophy carries with it clinical significance for the control of increased morbidity and mortality following physical inactivity. While major transcriptional events associated with muscle atrophy-recovery processes are the subject of active research on the gene level, the contribution of non-coding regulatory elements and alternative promoter usage is a major source for both the production of alternative protein products and new insights into the activity of transcription factors. We used the cap-analysis of gene expression (CAGE) to create a genome-wide atlas of promoter-level transcription in fast (m. EDL) and slow (m. soleus) muscles in rats that were subjected to hindlimb unloading and subsequent recovery. We found that the genetic regulation of the atrophy-recovery cycle in two types of muscle is mediated by different pathways, including a unique set of non-coding transcribed regulatory elements. We showed that the activation of “shadow” enhancers is tightly linked to specific stages of atrophy and recovery dynamics, with the largest number of specific regulatory elements being transcriptionally active in the muscles on the first day of recovery after a week of disuse. The developed comprehensive database of transcription of regulatory elements will further stimulate research on the gene regulation of muscle homeostasis in mammals.

Highlights

There are more than 600 different skeletal muscles in the human body, representing a complex and heterogeneous system capable of remodeling in response to mechanical load
Skeletal muscle is a heterogeneous system characterized by high plasticity
The soleus muscle is a postural slow-twitch muscle, which is preferentially affected by disuse, compared to other hindlimb muscles [14]

Summary

Introduction

There are more than 600 different skeletal muscles in the human body, representing a complex and heterogeneous system capable of remodeling in response to mechanical load. Muscle atrophy is associated with large changes in the interplay between protein synthesis and degradation, with the involvement of the activity of a number of genes collectively referred to as ‘atrogenes’, including members of the ubiquitin–proteasome and the autophagy–lysosomal pathways [3]. While major transcriptional events associated with muscle atrophy–recovery processes are elucidated to some extent on a gene level, little is known about the involvement of non-coding regulatory elements. The utilization of different promoters of the same gene is one of the major sources of both the production of alternative protein products and new deep insights into the activity of transcription factors [4]. Recent advances in transcriptomics reveal a key role of promoter- and enhancer-associated RNAs in the identification of cis-regulatory elements and the control of gene expression [5]

Methods

Results

Conclusion