Alternative Splicing of Transcription Factors Genes in Muscle Physiology and Pathology
Abstract
:1. Introduction
2. Myogenesis
2.1. Myogenesis During Embryonic Development
2.2. Post-Natal Myogenesis
3. Transcriptional Control of Skeletal Myogenesis
3.1. Families of Myogenic Transcription Factors
3.1.1. PAX3 and PAX7
3.1.2. SIX1 and SIX4
3.1.3. Myogenic Regulatory Factors
3.1.4. Repressors of MRFs
3.1.5. Co-Activators of MRFs
3.1.6. Myocyte Enhancer Factor-2 Proteins
3.2. Transcriptional Control of Specific Gene Expression Programs in Skeletal Muscle
3.2.1. Fetal Specific Gene Expression
3.2.2. Muscle Plasticity
3.2.3. Muscle Mass Homeostasis
4. Alternative Splicing in Skeletal Muscle
4.1. Alternative Splicing
4.2. Alternative Splicing in Skeletal Muscle Physiology
4.3. Aberrant Alternative Splicing in Skeletal Muscle Pathologies
5. Alternative Splicing of TFs in Skeletal Muscle Physiology and Muscle Diseases
5.1. Pax Family Genes
5.2. Myogenic Determination Factor Gene
5.3. Nuclear Factor 1/X Gene
5.4. Myocyte Enhancer Factor-2 Family Genes
5.5. Ubiquitous bHLH Proteins Class I
5.6. Inhibitor of DNA Binding (ID) Genes
6. Discussion
7. Conclusions and Future Directions
Acknowledgments
Conflicts of Interest
References
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Type of alternative splicing | TFs | Effects on TF |
Exon skipping/retention | NFIX1/2/3 | NFIX2: regulator of fetal muscle genes |
HEBα/β | HEBα: higher DNA binding and transcriptional activity
HEBβ: synergises with MyoD in early differentiation | |
PAX3Q+/− | PAX3Q-: stronger binding affinity and higher transcriptional activity | |
PAX7Q+/− | NA | |
PAX7GL+/− | PAX7GL-: increased binding affinity | |
PAX7-2 | PAX7-2: reduced transcriptional activity | |
E12/47
E2A-2/5 | E2A-2/5: dominant negative activity | |
MEF2A/B/C β | MEF2A/B/C β: higher transcriptional activity | |
TCF4 A-R | TCF4 AD1-containing isoforms: higher transcriptional activity | |
TCF4 FL/Δ | TCF4 FL/Δ: no correlation with transcriptional activity | |
Intron retention | TMyoD1α/β | NA |
ID1A/B | ID1A: inhibits the formation of E12/MYOD heterodimers.
ID1B: prevents the assembly of E12/E12 homodimers. | |
ID3/3L | ID3L: reduced antagonistic activity versus E47 | |
Mutually exclusive exons | MEF2A/B/C α1/α2 | MEF2A/B/C α1: repressor of terminal differentiation MEF2A/B/C α2: activator of terminal differentiation |
TCF4 A-R | TCF4 AD1-containing isoforms: higher transcriptional activity | |
Alternative 5’ or 3’ splice site usage | TCF4 A-R −/+ | TCF4 -/+: no correlation with transactivation activity |
MEF2C γ | MEF2C γ: reduced transcriptional activity | |
Alternative 3’ terminal exon | CiMDFa/b | CiMDFb: higher myogenic effector function |
PAX7A/B | PAX7A/B: myogenic commitment | |
PAX3A/B | NA | |
PAX3C/D | PAX3C: necessary for terminal myogenic differentiation
PAX3D: maintenance and/or proliferation of muscle precursor | |
Premature termination codon (PTC) | TMyoD1γ | TMyoD1γ: role in the regulation of TmyoD1 expression |
Family genes | Transcription factor | Splicing isoforms | Spliced region/domain | Species | References |
---|---|---|---|---|---|
Pax | PAX3 | Pax3Q+/Q− | Alternative splicing intron2/exon3 (N-terminus, linker region of the PD) | Zebrafish Mouse Human | [136,137,138,139,140,141] |
Pax3A/B | Termination at intron 4 (lack of HD and TA domains) | Mouse Human | [148] | ||
Pax3C/Pax3D | Alternative splicing of exon 8 (C-terminus) | Mouse Human | [146,149] | ||
PAX7 | Pax7Q+/Q− | Alternative splicing intron2/exon3 (N-terminus, linker region of the PD) | Mouse Human | [146,147] | |
Pax7GL+/GL− | Alternative splice at intron 3/exon 4 boundary (C-terminus PD subdomain) | Mouse Human | [137,139] | ||
Pax7A Pax7B | Termination at intron 8 Termination at exon9 (C-terminus) | Mouse Human | [146,147] | ||
Pax7-2 | Alternative splicing of exon8 (C-terminus) | Chicken | [150] | ||
bHLH (Class I and II) | MYOD | TMyoD1α/β/γ | Alternative retention of intron I and partial intron II | Takifugu rupripes | [151] |
CiMDFa/b | Extension to 3’UTR (Domain III) | Ciona intestinalis | [152] | ||
E2A/TCF3 | E12/E47 E2A-2/5 | Alternative inclusion of exon 15 (bHLH encoding exons - C-terminus) Exclusion of exons 3 and 4 (part of N-terminal AD1) | Mouse Human | [191,192,193] | |
HEB | Hebα/β | Inclusion of alternate exon (24-amino-acid ankyrin-like motif) | Rat Mouse Human | [194,195] | |
E2-2/TCF4 | Tcf4A-R Tcf4+/− FL/ΔTcf4 | Mutually exclusive 5’ exons (N-terminus) Alternative splice donor site selection at exon 18 (C-terminus) Exclusion/inclusion exons 8/9 (N-terminal NLS) | Mouse Human | [ 196,197] | |
HLH (Class V) | ID1 | Id1A/B | Inclusion/exclusion intron I (C-terminus) | Rat Mouse Human | [199] |
ID3 | Id3/3L | Inclusion/exclusion intron I (C-terminus) | Rat Mouse Human | [200] | |
Nfi | NFIX | m/h/ha/ch/r Nfix1 m Nfix2 m Nfix3 | Exon9 splicing Exon 7 and 9 splicing Exon 7 and 9 retention (C-terminus) | Chicken Hamster Mouse Rat Human | [73,159] |
Mef | MEF2A/C/D | Mef2aα1/α2 Mef2cα1/α2 Mef2dα1/α2 Mef2aβ Mef2cβ Mef2dβ Mef2cβ/γ | Alternative splicing exon α1/α2 Exclusion/inclusion exon β Exclusion/inclusion exon β or γ region | Mouse Human | [163,164,165,166,74,173,174,182] [167,175] [168,176,177,178,179] |
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Imbriano, C.; Molinari, S. Alternative Splicing of Transcription Factors Genes in Muscle Physiology and Pathology. Genes 2018, 9, 107. https://doi.org/10.3390/genes9020107
Imbriano C, Molinari S. Alternative Splicing of Transcription Factors Genes in Muscle Physiology and Pathology. Genes. 2018; 9(2):107. https://doi.org/10.3390/genes9020107
Chicago/Turabian StyleImbriano, Carol, and Susanna Molinari. 2018. "Alternative Splicing of Transcription Factors Genes in Muscle Physiology and Pathology" Genes 9, no. 2: 107. https://doi.org/10.3390/genes9020107
APA StyleImbriano, C., & Molinari, S. (2018). Alternative Splicing of Transcription Factors Genes in Muscle Physiology and Pathology. Genes, 9(2), 107. https://doi.org/10.3390/genes9020107