Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes
Abstract
:1. Introduction
2. Results
2.1. Many KLHL and KBTBD Genes Are Expressed Preferentially in SkM or Brain
2.2. Extensive Intragenic Promoter Chromatin and Overlapping DNA Hypomethylation Correlates with the Extremely High Expression of KLHL41 in Skeletal Muscle
2.3. Intragenic and Intergenic Enhancer Chromatin at KLHL40 or Its Neighbor, HHATL May Upregulate Both Genes or One or the Other Gene Depending on the Tissue
2.4. Skeletal Muscle-Specific Expression, Promoter Chromatin, and Enhancer Chromatin in KLHL30 and in KLHL38, a Paralog That Contains a Retrogene from KLHL30
2.5. Only Minor Skeletal Muscle-Associated Epigenetic Differences Occur in KEAP1 Consistent with Its Highest Expression in SkM But Otherwise Broad Tissue Expression Profile
2.6. The Neurogenesis-Associated ENC1 Gene Exhibited Much More Enhancer Chromatin and DNA Hypomethylation in Fetal than in Adult Brain
2.7. The Strong Brain-Specificity of KLHL32 Is Mirrored by Clusters of Intragenic Enhancer Chromatin Seen Only in Brain
2.8. KBTBD11, a Brain-Specific Gene, Has a Retrogene Overlaying a 3′ Promoter for a Novel Noncoding RNA Gene
2.9. Overview of Epigenetic Features Associated with the Studied KLHF Family Genes
3. Discussion
4. Methods
4.1. RNA-Seq for Tissues and Cells
4.2. Databases and Analyses Used for Epigenetics Studies
4.3. Alignments and Phylogenetic Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BS | bisulfite |
CAGE | 5′ Cap Analysis of Gene Expression |
CGI | CpG island |
ChIP-seq | chromatin immunoprecipitation with next-gen sequencing |
CTCF | CCCTC-binding factor |
Enh | enhancer |
FPKM | fragments per kilobase of exon per million reads mapped |
H3K27ac | Histone H3 lysine 27 acetylation |
H3K4me1 | histone H3 lysine 4 monomethylation |
H3K4me3 | histone H3 lysine 4 trimethylation |
LCL | lymphoblastoid cell line |
LMR | low methylated region |
Micro-C | a high-resolution type of chromatin capture analysis |
ncRNA | non-coding RNA |
NHLF | normal human lung fibroblasts |
ORF | open reading frame |
PBMC | peripheral blood mononuclear cells |
Prom | promoter |
SkM | skeletal muscle |
TAD | topologically associating domain |
TPM | transcripts per kilobase million |
TSS | transcription start site |
Txn | transcription |
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Description | TPM in SkM b | TPM Ratio: SkM to Median of Other Tissues | FPKM in Myoblasts | FPKM Ratio: Myoblasts to Median of Heterologous Cell Cultures c | FPKM Ratio: Myotubes to Myoblasts |
---|---|---|---|---|---|
KBTBD12 (Figure S4) | 15 | 13 | 0.3 | 0 | 2.8 |
KBTBD13d (Figure S6) | 1.5 | 25 | 0 | 0 | 0 |
KEAP1 (Figure 3) | 88 | 2.4 | 32 | 0.7 | 1.0 |
KLHL21 (Figure S10) | 84 | 3.3 | 31 | 0.6 | 1.4 |
KLHL30 (Figure 2) | 110 | 145 | 16 | 18.0 | 2.8 |
KLHL31 (Figure S2) | 18 | 59 | 5.6 | 5.8 | 872 |
KLHL33 (Figure S1) | 11 | 24 | 0 | 0 | 0 |
KLHL34 (Figure S3) | 8.5 | 113 | 0 | 0 | 0 |
KLHL38 (Figure 2) | 90 | 405 | 0.1 | 0 | 19 |
KLHL40 (Figure 1; Figure S5) | 303 | 3373 | 7.7 | #DIV/0! | 17 |
KLHL41 (Figure 1) | 3420 | 1946 | 104 | 1613 | 254 |
Description | Brain Tissue (Median TPM) | Ratio of Brain Tissue TPM to Median TPM of Non-Brain Tissues b | ||||
---|---|---|---|---|---|---|
Cortex c | Hippoc. c | Cerebel. c | Cortex | Hippoc. | Cerebel. | |
ENC1 (Figure 3) | 322 | 87 | 4.3 | 56 | 15 | 0.7 |
KBTBD11 (Figure 4) | 59 | 27 | 46 | 17 | 7.2 | 12 |
KLHL2 (Figure S9) | 47 | 47 | 21 | 3.2 | 45 | 39 |
KLHL32 (Figure 4) | 10 | 12 | 11 | 37 | 3.9 | 6.0 |
KLHL35d (Figure S9) | 3.3 | 1.6 | 2.5 | 8.0 | 13 | 2.9 |
KLHL4 (Figure S9) | 3.6 | 4.5 | 1.0 | 11 | 15 | 0.7 |
Epigenetic Profile Specifically Associated with SkM or Brain | Genes Preferentially Expressed in SkM (Some Also in Heart) | Genes Preferentially Expressed in Brain |
---|---|---|
Promoter chromatin upstream of TSS b | KLHL31, 33, 34 | None |
Promoter chromatin dnstrm of TSS b | KLHL30, 31, 33, 38, 41 | KLHL32, 35, KBTBD11 |
Broadening of a constitutively unmethylated region at the TSS | KLHL21, 33, 34, 40; KBTBD12 | KLHL2, 4, 32 (neurons c); ENC1, KBTBD11 (neurons/fetal brain) |
DNA hypomethylation upstream of TSS b | KLHL30, 31, 33, 34, 38, 40, KBTBD13 | KLHL32 (neurons) |
DNA hypomethylation dnstrm of TSS b | KLHL21, 30, 31, 33, 41; KBTBD12 | KLHL2, 4, 32 (neurons) |
Super-enhancer | KLHL 21, 30, 31, 38, 40, 41 | ENC1 |
Intragenic enhancer chromatin | KLHL21, 30, 31, 32, 33, 34, 38, 40, 41; KEAP1; KBTBD12, 13 | KLHL2, 35; KBTBD11, ENC1 |
Gene-upstream enhancer chromatin | KLHL21, 30, 31, 33, 34, 38, 40, 41 | KLHL32, KBTBD11, ENC1 (neurons/fetal brain) |
Gene-downstream enhancer chromatin | KLHL21, 38, KBTBD12 | KBTBD11, ENC1 (fetal brain) |
DNA hypomethylation in enhancer chromatin | KLHL21, 30, 31, 33, 34, 38, 40, 41, KBTBD12, 13 | KLHL2 (hippocampus, anterior caudate) |
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Ehrlich, K.C.; Baribault, C.; Ehrlich, M. Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes. Int. J. Mol. Sci. 2020, 21, 8394. https://doi.org/10.3390/ijms21218394
Ehrlich KC, Baribault C, Ehrlich M. Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes. International Journal of Molecular Sciences. 2020; 21(21):8394. https://doi.org/10.3390/ijms21218394
Chicago/Turabian StyleEhrlich, Kenneth C., Carl Baribault, and Melanie Ehrlich. 2020. "Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes" International Journal of Molecular Sciences 21, no. 21: 8394. https://doi.org/10.3390/ijms21218394