Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels

AbstractThe rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.

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HIRA stabilizes skeletal muscle lineage identity

Nature Communications ◽

10.1038/s41467-021-23775-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joana Esteves de Lima ◽

Reem Bou Akar ◽

Léo Machado ◽

Yuefeng Li ◽

Bernadette Drayton-Libotte ◽

...

Keyword(s):

Skeletal Muscle ◽

Cell Lineage ◽

Promoter Regions ◽

Cell Fates ◽

Regulatory Regions ◽

Muscle Stem Cells ◽

Adult Mice ◽

H3k4me3 Mark ◽

Muscle Genes ◽

Muscle Gene

AbstractThe epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

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Specific phosphorylation of a COOH-terminal site on the full-length form of the alpha 1 subunit of the skeletal muscle calcium channel by cAMP-dependent protein kinase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)41972-2 ◽

1992 ◽

Vol 267 (23) ◽

pp. 16100-16105

Author(s):

E.I. Rotman ◽

K.S. De Jongh ◽

V Florio ◽

Y Lai ◽

W.A. Catterall

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Calcium Channel ◽

Full Length ◽

Dependent Protein Kinase ◽

Camp Dependent Protein Kinase ◽

Dependent Protein ◽

Muscle Calcium ◽

Terminal Site

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Myostatin expression in porcine tissues: tissue specificity and developmental and postnatal regulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.4.r1265 ◽

1998 ◽

Vol 275 (4) ◽

pp. R1265-R1273 ◽

Cited By ~ 34

Author(s):

Shaoquan Ji ◽

R. L. Losinski ◽

S. G. Cornelius ◽

G. R. Frank ◽

G. M. Willis ◽

...

Keyword(s):

Skeletal Muscle ◽

Mammary Gland ◽

Birth Weight ◽

Low Birth Weight ◽

Tissue Specificity ◽

Muscle Growth ◽

Mrna Abundance ◽

Longissimus Muscle ◽

Gland Development ◽

Level 2

The objective of this study was to establish the developmental pattern and tissue specificity of porcine myostatin expression and to evaluate expression in skeletal muscle during circumstances in which muscle growth was altered. Northern blot analysis revealed two transcripts (1.5 and 0.8 kb). Myostatin mRNA was detected in whole fetuses at 21 and 35 days and was markedly increased ( P < 0.05) by 49 days. At birth, mRNA abundance in longissimus muscle had declined significantly ( P < 0.05) from that at day 105 of gestation and continued to decrease ( P < 0.05) to its lowest level 2 wk postnatally (4 kg body wt). Myostatin expression was higher ( P < 0.05) at 55, 107, and 162 kg body wt than at 4 kg body wt. Postnatally, myostatin mRNA was detected in skeletal muscle and mammary gland. Expression at birth was 65% higher ( P < 0.04) in longissimus muscle of low-birth-weight piglets (0.57 ± 0.052 kg body wt) vs. normal (1.37 ± 0.077 kg body wt) littermates, irrespective of gender. However, suppression of longissimus muscle growth by food deprivation (3 days) did not alter ( P > 0.15) myostatin expression in either 4- or 7-wk-old piglets. Additionally, myostatin mRNA abundance was not changed by porcine growth hormone administration in growing animals. These data indicate that myostatin expression in skeletal muscle peaks prenatally and that greater expression is associated with low birth weight. Expression in mammary gland indicates a possible role for myostatin in mammary gland development and/or lactation.

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Nanopore direct RNA sequencing maps the complexity of Arabidopsis mRNA processing and m6A modification

eLife ◽

10.7554/elife.49658 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 43

Author(s):

Matthew T Parker ◽

Katarzyna Knop ◽

Anna V Sherwood ◽

Nicholas J Schurch ◽

Katarzyna Mackinnon ◽

...

Keyword(s):

Rna Sequencing ◽

Single Molecule ◽

Tail Length ◽

Transcript Abundance ◽

Mrna Processing ◽

Full Length ◽

Transcription Start Sites ◽

Model Plant Arabidopsis Thaliana ◽

Defective Rna ◽

A Site

Understanding genome organization and gene regulation requires insight into RNA transcription, processing and modification. We adapted nanopore direct RNA sequencing to examine RNA from a wild-type accession of the model plant Arabidopsis thaliana and a mutant defective in mRNA methylation (m6A). Here we show that m6A can be mapped in full-length mRNAs transcriptome-wide and reveal the combinatorial diversity of cap-associated transcription start sites, splicing events, poly(A) site choice and poly(A) tail length. Loss of m6A from 3’ untranslated regions is associated with decreased relative transcript abundance and defective RNA 3′ end formation. A functional consequence of disrupted m6A is a lengthening of the circadian period. We conclude that nanopore direct RNA sequencing can reveal the complexity of mRNA processing and modification in full-length single molecule reads. These findings can refine Arabidopsis genome annotation. Further, applying this approach to less well-studied species could transform our understanding of what their genomes encode.

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Characterization, Tissue Expression, and Imprinting Analysis of the Porcine CDKN1C and NAP1L4 Genes

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/946527 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Shun Li ◽

Juan Li ◽

Jiawei Tian ◽

Ranran Dong ◽

Jin Wei ◽

...

Keyword(s):

Skeletal Muscle ◽

Small Intestine ◽

Candidate Genes ◽

Tissue Specificity ◽

Mammalian Species ◽

Tissue Expression ◽

Chromosome 2 ◽

Porcine Chromosome ◽

Rt Pcr ◽

Lung And Kidney

CDKN1C and NAP1L4 in human CDKN1C/KCNQ1OT1 imprinted domain are two key candidate genes responsible for BWS (Beckwith-Wiedemann syndrome) and cancer. In order to increase understanding of these genes in pigs, their cDNAs are characterized in this paper. By the IMpRH panel, porcine CDKN1C and NAP1L4 genes were assigned to porcine chromosome 2, closely linked with IMpRH06175 and with LOD of 15.78 and 17.94, respectively. By real-time quantitative RT-PCR and polymorphism-based method, tissue and allelic expression of both genes were determined using F1 pigs of Rongchang and Landrace reciprocal crosses. The transcription levels of porcine CDKN1C and NAP1L4 were significantly higher in placenta than in other neonatal tissues (P<0.01) although both genes showed the highest expression levels in the lung and kidney of one-month pigs (P<0.01). Imprinting analysis demonstrated that in pigs, CDKN1C was maternally expressed in neonatal heart, tongue, bladder, ovary, spleen, liver, skeletal muscle, stomach, small intestine, and placenta and biallelically expressed in lung and kidney, while NAP1L4 was biallelically expressed in the 12 neonatal tissues examined. It is concluded that imprinting of CDKN1C is conservative in mammals but has tissue specificity in pigs, and imprinting of NAP1L4 is controversial in mammalian species.

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Elevation of MicroRNA-126 Levels in Intracranial Aneurysm and Bioinformatic Analysis of Potential Molecular Mechanisms

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2572 ◽

2021 ◽

Vol 11 (4) ◽

pp. 573-579

Author(s):

Pan Huang ◽

Min Xu ◽

Xiao-Ying He

Keyword(s):

Intracranial Aneurysm ◽

Peripheral Blood ◽

Target Gene ◽

Molecular Mechanisms ◽

Target Genes ◽

Kegg Pathway ◽

Bioinformatic Analysis ◽

Control Group ◽

Potential Target ◽

Fas Signaling

The study is to investigation of microRNA-126 levels in patients with intracranial aneurysm and bioinformatic analysis of the molecular mechanisms involved. A total of 166 patients with ICA who were hospitalized or examined in our hospital from September 2015 to December 2017 were used as the experimental group (ICA group). This group included 120 patients with unruptured intracranial aneurysm (UICA; UICA group) and 46 patients with ruptured intracranial aneurysm (RICA); RICA group). The UICA group was further subdivided into 42 surgical groups (S group) and 78 nonsurgical groups (NS group). Sixty-three normal people without intracranial aneurysms were selected as the control group. RT-PCR was used to quantitatively detect the relative expression of microRNA- 126 in peripheral blood mononuclear cells at the time of admission and immediately after surgery. The UCSC database was used to analyze the gene locus and homology of microRNA-126. The TargetScan database and CoMeTa database were used to predict the potential target genes of microRNA-126. The DAVID database was used to enrich the function of potential target genes of microRNA-126 (GO enrichment) and KEGG pathway enrichment for analysis. The expression level of microRNA-126 in peripheral blood was significantly higher in the ICA group than in the control group (P <0.01), significantly higher in the RICA group than in the UICA group (P <0.05). Expression was also higher in the NS group than in the S group but the difference was nonsignificant (P >0.05). A total of 15 potential target genes including ITGA6, CRK, PCDH7, and ADAM9 were identified through the target gene prediction software and GO analysis and KEGG pathway analysis showed that the function of the microRNA-126 target gene was mainly focused on protein binding and the FAS signaling pathway. In Conclusion the microRNA-126 is up-regulated in ICA patients and affects ICA by regulating multiple target genes in the FAS signaling pathway.

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Complete sequence and in vitro expression of a tissue-specific phosphatidylinositol-linked N-CAM isoform from skeletal muscle

Development ◽

10.1242/dev.104.1.165 ◽

1988 ◽

Vol 104 (1) ◽

pp. 165-173 ◽

Cited By ~ 1

Author(s):

C.H. Barton ◽

G. Dickson ◽

H.J. Gower ◽

L.H. Rowett ◽

W. Putt ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Cell Surface ◽

Protein Sequence ◽

Single Copy ◽

In Vitro Transcription ◽

Full Length ◽

Covalent Attachment ◽

Size Difference

Neural cell adhesion molecules (N-CAMs) are a family of cell surface sialoglycoproteins encoded by a single copy gene. A full-length cDNA clone that encodes a nontransmembrane phosphatidylinositol (PI) linked N-CAM of Mr 125 × 10(3) has been isolated from a human skeletal muscle cDNA library. The deduced protein sequence encodes a polypeptide of 761 amino acids and is highly homologous to the N-CAM isoform in brain of Mr 120 × 10(3). The size difference between the 125 × 10(3). The size difference between the 125 × 10(3) Mr skeletal muscle form and the 120 × 10(3) Mr N-CAM form from brain is accounted for by the insertion of a block of 37 amino acids called MSD1, in the extracellular domain of the muscle form. Transient expression of the human cDNA in COS cells results in cell surface N-CAM expression via a putative covalent attachment to PI-containing phospholipid. Linked in vitro transcription and translation experiments followed by immunoprecipitation with anti-N-CAM antibodies demonstrate that the full-length clone of 761 amino acid coding potential produces a core polypeptide of Mr 110 × 10(3) which is processed by microsomal membranes to yield a 122 × 10(3) Mr species. Taken together, these results demonstrate that the cloned cDNA sequence encodes a lipid-linked, PI-specific phospholipase C releasable surface isoform of N-CAM with core glycopeptide molecular weight corresponding to the authentic muscle 125 × 10(3) Mr N-CAM isoform. This is the first direct correlation of cDNA and deduced protein sequence with a known PI-linked N-CAM isoform from skeletal muscle.

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Activation of RNA metabolism-related genes in mouse but not human tissues deficient in SMN

Physiological Genomics ◽

10.1152/physiolgenomics.00134.2005 ◽

2006 ◽

Vol 24 (2) ◽

pp. 97-104 ◽

Cited By ~ 15

Author(s):

Robert Olaso ◽

Vandana Joshi ◽

Julien Fernandez ◽

Natacha Roblot ◽

Sabrina Courageot ◽

...

Keyword(s):

Skeletal Muscle ◽

Motor Neuron ◽

Expression Profiles ◽

Neuromuscular Disorders ◽

Gene Activation ◽

Rna Metabolism ◽

Homozygous Deletion ◽

Full Length ◽

Pcr Analysis ◽

Severe Motor

Mutations of the survival of motor neuron gene ( SMN1) are responsible for spinal muscular atrophies (SMA), a frequent recessive autosomal motor neuron disease. SMN is involved in various processes including RNA metabolism. However, the molecular pathway linking marked deficiency of SMN to SMA phenotype remains unclear. Homozygous deletion of murine Smn exon 7 directed to neurons or skeletal muscle causes severe motor axonal or myofiber degeneration, respectively. With the use of cDNA microarrays, expression profiles of 8,400 genes were analyzed in skeletal muscle and spinal cord of muscular and neuronal mutants, respectively, and compared with age-matched controls. A high proportion of genes (20 of 429, 5%) was involved in pre-mRNA splicing, ribosomal RNA processing, or RNA decay, and 18 of them were upregulated in mutant tissues. By analyzing other neuromuscular disorders, we showed that most of them (14 of 18) were specific to the SMN defect. Quantitative PCR analysis of these transcripts showed that gene activation was an early adaptive response to the lack but not reduced amount of full-length SMN in mouse mutant tissues. In human SMA tissues, activation of this program was not observed, which could be ascribed to the reduction but not the absence of full-length SMN.

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