The complex genetics of human insulin-like growth factor 2 are not reflected in public databases

Rotwein, Peter

doi:10.1074/jbc.ra117.001573

Cited by 24 publications

(67 citation statements)

References 73 publications

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“…Human IGF2 -H19 locus. The human IGF2 -H19 locus on chromosome 11p15.5 contains five protein-coding genes and several genes expressing noncoding RNAs (60) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…The following genomes were searched: bonobo (Pan paniscus, Bonobo panpan1.1), chimpanzee (Pan troglodytes, Pan_tro_3.0), gibbon (Nomascus leucogenys, Nlue_3.0), gorilla (Gorilla gorilla, gorGor4), macaque (Macaca mulatta, Mmul_8.0.1), marmoset (Callithrix jacchus, C_jacchus3.2.1), mouse (Mus musculus, genome assembly GRCm38), mouse lemur (Microcebus murinus, Mmur_3.0), olive baboon (Papio anubis, Pa-pAnu3.0), and orangutan (Pongo abelii, PPYG2). The highest scoring Green circles represent the imprinting control region (ICR), which is located adjacent to H19 (19,50,75), and orange ovals depict the 9 human homologs of the 10 distal enhancers that were identified and functionally mapped in the mouse genome (30,60). B: detailed view of human IGF2 and H19 genes, with exons as boxes (10 for IGF2 and 6 for H19), and introns and flanking DNA as horizontal lines.…”

Section: Methodsmentioning

confidence: 99%

“…Data on human H19 gene expression were extracted from the Portal for the Genotype-Expression Project (GTEx v7, https://www.gtexportal.org/home/), using the exon expression module and analyzing alternatively spliced transcripts, which were categorized by the presence of specific exons or exon segments. Analysis of human IGF2 gene expression with the same database has been reported recently (60). Examination of H19 gene expression in different primates was conducted using the Sequence Read Archive of the National Center for Biotechnology Information (SRA NCBI; https://www.ncbi.nlm.nih.gov/sra), the NCBI AceView program (https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/) (68), and the Nonhuman Primate Reference (http://www.nhprtr.org/) (48,51).…”

Section: Methodsmentioning

confidence: 99%

“…As this promoter is expressed from both alleles in some human tissues and thus appears not to be imprinted (74), it also had been postulated that lack or loss of imprinting control governed maintenance of IGF2 activity in adult humans (74). Recent observations have demonstrated that this idea appears to be incorrect, as several IGF2 gene promoters are active in multiple adult human tissues (60). Thus, the molecular mechanisms responsible for main-taining IGF2 mRNA biosynthesis and protein production throughout life in humans or attenuating it in mice have not been established.…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances in molecular genetics present opportunities for gaining new insights into human physiology, disease predisposition, and human origins and evolution (1,34,53) through analysis of information found in genomic databases (39). Yet understanding these data has been challenging, in part because of problems of annotation and difficulties in extracting and verifying accuracy and completeness of the information, as was shown recently for human IGF2 (60). The present analysis was undertaken to learn more about the IGF2 -H19 locus in primates, the evolutionarily closest human relatives (58), with the goal of gaining preliminary insight into processes that may have imposed or limited constraints on locus regulation and gene function during primate speciation.…”

Section: Introductionmentioning

confidence: 99%

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Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates

Rotwein

2018

Physiological Genomics

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Insulin-like growth factor 2 (IGF2), a small, secreted protein, is critical for fetal and prenatal growth in humans and other mammals. The IGF2 gene and its mouse homolog comprise part of a conserved linkage group that is regulated by parental imprinting, with IGF2/ Igf2 being expressed from the paternal chromosome, and the adjacent H19 gene from the maternal chromosome. By using information extracted from public genomic and gene expression databases, I have now analyzed this locus in nine nonhuman primate species representing over 60 million years of evolutionary divergence from a common progenitor. Both IGF2 and H19 genes and the entire locus have been conserved among these primates. Each primate IGF2 gene except for gibbon and marmoset is composed of 10 exons and contains five potential promoters, each with distinctive 5'-untranslated exons. Similarly, except for marmoset and mouse lemur, H19 consists of six exons and has two promoters. DNA sequence conservation is high, not only in orthologous exons and promoters, but also in a putative imprinting control region located 5' to H19 and in multiple potential distal enhancer elements found 3' to H19. Collectively, these results support the hypothesis that common regulatory processes shaped the IGF2 - H19 locus before the onset of primate speciation more than 85 million years ago. This study also leads to the conclusion that inaccuracies in data presentation in genetic repositories could limit our ability to develop novel insights about roles of individual genes and multigene loci in mammalian physiology and disease.

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“…Human IGF2 -H19 locus. The human IGF2 -H19 locus on chromosome 11p15.5 contains five protein-coding genes and several genes expressing noncoding RNAs (60) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates

Rotwein

2018

Physiological Genomics

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Fear, violence, inequality, and stunting in Guatemala

Bogin

2021

Am J Hum Biol

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Background Stunting is defined by the public health community as a length‐ or height‐for‐age <−2 SD of a growth standard or reference and is claimed to be caused by poor nutrition, repeated infection, and inadequate psychosocial stimulation. Material and Methods Stunting is common at all income levels in middle‐ and low‐income countries. At the higher income levels, stunting is unlikely to be caused by nutrient deficiency or infectious disease. Results In Guatemala, 17% of <5‐year‐olds in the highest family income quintile are stunted. Guatemala has a history of violence from armed conflict, current‐day social and economic inequalities, government corruption, and threat of kidnapping for the wealthiest families. Discussion and Conclusion The high level of persistent violence creates an ecology of fear, an extreme range of inequalities in Social‐Economic‐Political‐Emotional resources, and biosocial stress that inhibits skeletal growth and causes stunting for people of all income levels.

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Grandmaternal betaine supplementation enhances hepatic IGF2 expression in F2 rat offspring through modification of promoter DNA methylation

et al. 2019

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BACKGROUND: We reported previously that maternal betaine promotes hepatic insulin-like growth factor (IGF2) expression in F1 offspring rats through hypermethylation of the IGF2/H19 imprinting control region (ICR). It remains unknown whether this acquired trait can be transmitted to the F2 generation. This study aimed to determine whether dietary betaine supplementation to grand dams affects the hepatic IGF2 expression in F2 rat offspring and how it is related to alterations in DNA methylation. F2 rat offspring derived from grand dams fed basal or betaine-supplemented diet (10 g kg −1 ) were examined at weaning. Serum IGF2 concentration was measured with enzyme-linked immunosorbent assay (ELISA). Hepatic expression of IGF2, together with other proliferation and apoptosis markers, was determined by using quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemistry. The methylation status of the IGF2/H19 ICR and the promoters of IGF2 gene were detected by methylated DNA immunoprecipitation quantitative polymerase chain reaction (MeDIP-qPCR). RESULTS: The maternal betaine-induced up-regulation of hepatic IGF2 expression in F1 ratoffspring was transmitted to the F2 generation. The F2 rats from the betaine group demonstrated enhanced hepatic IGF2 expression at both mRNA and protein levels, in association with higher serum IGF2 concentration. No alterations were observed in the ICR methylation of the IGF2/H19 locus, and hypomethylation was detected in promoters of IGF2 gene in betaine group. CONCLUSION: These results indicate that maternal betaine enhances hepatic IGF2 expression in F2 rat offspring through modification of DNA methylation on IGF2 promoters.Immunohistochemical staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay Proliferating cell nuclear antigen and IGF2 immunoreactive cells were stained with immunohistochemistry in liver sections as

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The complex genetics of human insulin-like growth factor 2 are not reflected in public databases

Cited by 24 publications

References 73 publications

Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates

Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates

Fear, violence, inequality, and stunting in Guatemala

Grandmaternal betaine supplementation enhances hepatic IGF2 expression in F2 rat offspring through modification of promoter DNA methylation

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