Epigenetics of Mitochondria-Associated Genes in Striated Muscle.

Kenneth C Ehrlich,Hong-Wen Deng,Melanie Ehrlich

doi:10.3390/epigenomes6010001

Abstract

Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many showed strong correlations between their tissue-specific transcription levels, and their tissue-specific promoter, enhancer, or open chromatin as well as their DNA hypomethylation. Their striated muscle-specific enhancer chromatin was inside, upstream, or downstream of the gene, throughout much of the gene as a super-enhancer (CKMT2, SLC25A4, and ACO2), or even overlapping a neighboring gene (COX6A2, COX7A1, and COQ10A). Surprisingly, the 3′ end of the 1.38 Mb PRKN (PARK2) gene (involved in mitophagy and linked to juvenile Parkinson’s disease) displayed skeletal muscle/myoblast-specific enhancer chromatin, a myoblast-specific antisense RNA, as well as brain-specific enhancer chromatin. We also found novel tissue-specific RNAs in brain and embryonic stem cells within PPARGC1A (PGC-1α), which encodes a master transcriptional coregulator for mitochondrial formation and metabolism. The tissue specificity of this gene’s four alternative promoters, including a muscle-associated promoter, correlated with nearby enhancer chromatin and open chromatin. Our in-depth epigenetic examination of these genes revealed previously undescribed tissue-specific enhancer chromatin, intragenic promoters, regions of DNA hypomethylation, and intragenic noncoding RNAs that give new insights into transcription control for this medically important set of genes.

Highlights

Striated muscle consists of skeletal muscle (SkM), the largest organ in the body, and heart muscle, whose malfunction is responsible for approximately 30% of deaths globally [1]
We found that two regions of enhancer chromatin at the 3 end of PRKN in myoblasts were associated with novel antisense (AS) intronic transcripts (Figure 6E, boxes, and Figure S5)
There were strong associations of the tissue-specific enhancer and promoter chromatin profiles with tissue-specific expression profiles. This epigenetic/transcription correlation indicates that transcription control plays a major role in determining the steady-state levels of mRNA for the studied genes. If this were not the case and tissue-specific posttranscriptional control had been superimposed on broad transcription profiles, we would not have seen the many examples of tissue-specific promoter/enhancer/open chromatin/DNA methylation profiles corresponding to expression profiles

Summary

Introduction

Striated muscle consists of skeletal muscle (SkM), the largest organ in the body, and heart muscle, whose malfunction is responsible for approximately 30% of deaths globally [1]. This type of muscle is characterized by repeated highly organized units, which are called sarcomeres, and contain myosin and actin filaments that allow muscle to contract [2]. The progenitor cells for SkM formation and repair are myoblasts, which, upon differentiation, can develop into multinucleated myotubes or fuse with multinucleated muscle fibers [6]. Multiple types of cardiac progenitor cells from different developmental lineages are involved in heart formation [8] and these lineages diverge according to the chamber of the heart [9]. Morphological and physiological differences in heart chambers and in SkM type (and fiber type [11,12]) are accompanied by differences in transcription profiling, cardiac muscle forms one interrelated group distinct from several SkM subgroups [3]

Methods

Results

Discussion

Conclusion