Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome

Li, Yahan; Boadu, Frimpong; Highsmith, Max; Hagen, Darren E.; Cheng, Jianlin; Rivera, Rocío Melissa

doi:10.1016/j.isci.2022.104269

Cited by 7 publications

(23 citation statements)

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“…According to our analysis and previous result, we confirmed the dysregulation of genes known to be associated with overgrowth: IGF2R, GNAS, DNMT3A, and CDKN1C [19]. IGF2R was downregulated in ART-LOS muscle and low levels of IGF2R has been identified in both bovine and ovine fetal overgrowth due to IVF [9,86]. GNAS was upregulated in the ART-LOS muscle, which is consistent with hypomethylation of the GNAS loci that has been observed in Beckwith-Wiedemann syndrome [87].…”

Section: De Trfs Target Transcripts In Los Individualssupporting

confidence: 88%

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Goldkamp

Rivera

et al. 2022

Preprint

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Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5-tRFs in muscle and 5-halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R=0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

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Section: De Trfs Target Transcripts In Los Individualssupporting

confidence: 88%

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Goldkamp

Rivera

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…According to our analysis and previous result, we confirmed the dysregulation of genes known to be associated with overgrowth: IGF2R , GNAS , DNMT3A , and CDKN1C ( Chen et al, 2015 ). IGF2R was downregulated in ART-LOS muscle and low levels of IGF2R has been identified in both bovine and ovine fetal overgrowth due to IVF ( Young et al, 2001 ; Li et al, 2022 ). GNAS was upregulated in the ART-LOS muscle, which is consistent with hypomethylation of the GNAS loci that has been observed in Beckwith-Wiedemann syndrome ( Bliek et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Goldkamp

Rivera

et al. 2022

Front. Genet.

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Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance.Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6).Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

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“…I also observed genomic location-based clustering tendency of misregulated genes in LOS. This study has been published in the Journal iScience (https://doi.org/10.1016/j.isci.2022.104269) (Li et al, 2022). In Chapter 3, I determined that bovine SLOS has DNA methylation defects with some similarities and differences when compared to ART-LOS.…”

Section: List Of Tablesmentioning

confidence: 99%

“…These misregulated miRNAs exhibit clustering tendency in their genomic locations and could affect the expression of thousands of gene at protein level given their roles in translation inhibition. Loss-of-imprinting at imprinted domains in bovine LOS have been reported for IGF2R, KCNQ1, IGF2, PLAGL1, PEG3, and DLK1 (Chen et al, 2013(Chen et al, , 2015(Chen et al, , 2017Hori et al, 2010;Li et al, 2019aLi et al, , 2022Sangalli et al, 2014;Su et al, 2011aSu et al, , 2011b. Aberrations of histone modifications are often associated with somatic cell nuclear transfer (SCNT) derived bovine fetuses (Arnold et al, 2017;Lin et al, 2008;Santos et al, 2003), which is partially due to original somatic histone modifications escaping reprogramming (Wee et al, 2006).…”

Section: Molecular Aberrations In Losmentioning

confidence: 99%

“…Of note, in this study we only included the promoters of protein coding genes and long non-coding RNAs (lncRNAs) since the location of promoters for small ncRNA are not well characterized in bovine (Li et al, 2010). We also compared the DMRs identified here with those previously published for ART-LOS skeletal muscle and skin fibroblast cells (Chen et al, 2017;Li et al, 2022) and identified an overlap of 22 and 134 DMRs, respectively (Figure 2. A-B).…”

Section: Genomic Context Of Differentially Methylated Regions In Slos...mentioning

confidence: 99%

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Involvement of aberrant chromosome architecture and locus-specific vulnerability to DNA methylation epimutations in bovine large offspring syndrome

Li¹

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Large/abnormal offspring syndrome (LOS/AOS) and Beckwith-Wiedemann syndrome (BWS) are similar congenital overgrowth syndromes which occur naturally in ruminants and humans, respectively. The incidence of these syndromes increases when offspring are conceived with the use of assisted reproductive technologies (ART; i.e. in vitro oocyte maturation, in vitro fertilization, and embryo culture). Molecular defects reported in both syndromes include global gene misregulation, DNA methylome epimutations, and disruption of genomic imprinting (parental-allele-specific gene expression). Although we have reported that bovine LOS occurs spontaneously (SLOS) based on phenotypic similarities to ART-LOS, to date no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. One goal of my dissertation research is to characterize DNA methylation profiles in bovine SLOS and ART-LOS to determine whether there are conserved genomic loci with DNA methylation defects between these overgrowth conditions. In addition, while it is known that LOS is characterized by global alterations in DNA methylation, it is largely unknown how altered DNA methylation drives the development of LOS, as the methylation errors (i.e., differentially methylated regions; DMRs) observed in the syndrome only explain [less than] 4 percent of the gene misregulation in short range (the flanking 20,000 DNA bases from the DMR). Therefore, another goal of my dissertation research is to determine whether long-range regulatory mechanisms of gene expression, such as chromosome architecture, is altered in LOS as a result of aberrant DNA methylation. In this dissertation, Chapter 1 is the literature review and will introduce epigenetic regulation of gene expression including chromosome architecture and clinical features and molecular findings of LOS and BWS. Chapter 2 and 3 are the research chapters. In Chapter 2, I characterize allele-specific chromosome architecture of IGF2R imprinted domain in fibroblast cells derived from control bovine fetuses and identified disrupted chromosome architecture in LOS. I also observed genomic location-based clustering tendency of misregulated genes in LOS. This study has been published in the Journal iScience (https://doi.org/10.1016/j.isci.2022.104269) (Li et al., 2022). In Chapter 3, I determined that bovine SLOS has DNA methylation defects with some similarities and differences when compared to ART-LOS. I also identified vulnerable genomic loci for DNA methylation defects in LOS, which could serve as molecular markers for the diagnosis of the syndrome during early pregnancy. This study has been published in the journal Epigenetics (https://doi.org/10.1080/15592294.2022.2067938). Chapter 4 is the general discussion in which my research findings are incorporated into the general knowledge of the field and implications and directions of future studies are discussed. In Appendix 1, I briefly introduce our ongoing Hi-C (global chromosome architecture), methylome and transcriptome project in which samples from LOS and BWS will be analyzed together to further shed light into the etiology of these syndromes, knowledge that will equally help Agriculture and Biomedicine. I anticipate submitting this manuscript for peer review and publication in July of 2022, thus becoming the third primary literature manuscript from my dissertation research. Appendix 2 is a review paper in which I am main contributor author published in Veterinary Clinics of North America: Food Animal Practice in 2019 (PMID: 31103180, https://doi.org/10.1016/j.cvfa.2019.02.007). This review summarized clinical and molecular findings in LOS and for the first time reported the existence of SLOS. Lastly, Appendix 3 summarizes my contributions of five other publications in which I collaborated with groups in the Division, at Mizzou, and other Academic institutions in the USA during my tenure as a PhD student.

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Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome

Cited by 7 publications

References 78 publications

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome

Involvement of aberrant chromosome architecture and locus-specific vulnerability to DNA methylation epimutations in bovine large offspring syndrome

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