Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Yamamoto, Ryō; Chung, Ryan; Vazquez, Juan Manuel; Sheng, Huanjie; Steinberg, Philippa L.; Ioannidis, Nilah M.; Sudmant, Peter H.

doi:10.1101/2021.11.16.468753

Cited by 4 publications

(5 citation statements)

References 39 publications

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“…In addition, of interest to us is the degree of inheritability of gene expression regulation expressed in their variance, as has been shown previously [32]. We are also interested in what changes occur with the baseline, or inherited diversity of epigenetic gene tuning in the genome groups we study, based on methylation data.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation meta-analysis confirms the division of the genome into two functional groups

Salnikov¹,

Goldberg

Sukumaran

et al. 2022

Preprint

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Based on a meta-analysis of human genome methylation data, we tested a theoretical model in which aging is explained by the redistribution of limited resources in cells between two main tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation, provided by the (IntG) integrative gene group. A meta-analysis of methylation of 100 genes, 50 in the HG group and 50 in IntG, showed significant differences ( p<0.0001) between our groups in the level of absolute methylation values of genes bodies and its promoters. We showed a reliable decrease of absolute methylation values in IntG with rising age in contrast to HG, where this level remained constant. The one-sided decrease in methylation in the IntG group is indirectly confirmed by the dispersion data analysis, which also decreased in the genes of this group. The imbalance between HG and IntG in methylation levels suggests that this IntG-shift is a side effect of the ontogenesis grownup program and the main cause of aging. The theoretical model of functional genome division also suggests the leading role of slow dividing and post mitotic cells in triggering and implementing the aging process.

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Section: Introductionmentioning

confidence: 99%

DNA methylation meta-analysis confirms the division of the genome into two functional groups

Salnikov¹,

Goldberg

Sukumaran

et al. 2022

Preprint

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“…The impact of genomic instability, epigenetic alterations, and altered cellular communication, all hallmarks of aging, are not exclusive to genes and likely impact global expression (López-Otín et al, 2013;Yamamoto et al, 2022). The interconnectedness between repeat and gene expression has largely been understudied in the context of aging until recently.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, repeat-dense modules correlate with CERAD and Braak scores, suggesting a relationship between repeat expression and neuropathological hallmarks of disease, independent of age (Yamamoto et al, 2022). For example, the repeats in Light Cyan module in caudate consists exclusively of LINE-1 elements, sequences harboring conserved potential G-quadruplex (G4) forming sequences in their 3' end which are associated with increased retrotransposition (Sahakyan et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Lifespan analysis of repeat expression reveals age-dependent upregulation of HERV-K in the neurotypical human brain

Evans,

Feltrin,

Benjamin

et al. 2024

Preprint

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DNA repetitive sequences (or repeats) comprise over 50% of the human genome and have a crucial regulatory role, specifically regulating transcription machinery. The human brain is the tissue with the highest detectable repeat expression and dysregulations on the repeat activity are related to several neurological and neurodegenerative disorders, as repeat-derived products can stimulate a pro-inflammatory response. Even so, it is unclear how repeat expression acts on the aging neurotypical brain. Here, we leverage a large postmortem transcriptome cohort spanning the human lifespan to assess global repeat expression in the neurotypical brain. We identified 21,696 differentially expressed repeats (DERs) that varied across seven age bins (Prenatal; 0-15; 16-29; 30-39; 40-49; 50-59; 60+) across the caudate nucleus (n=271), dorsolateral prefrontal cortex (n=304), and hippocampus (n=310). Interestingly, we found that long interspersed nuclear elements and long terminal repeats (LTRs) DERs were the most abundant repeat families when comparing infants to early adolescence (0-15) with older adults (60+). Of these differentially regulated LTRs, we identified 17 shared across all brain regions, including increased expression of HERV-K-int in older adult brains (60+). Co-expression analysis from each of the three brain regions also showed repeats from the HERV subfamily were intramodular hubs in its subnetworks. While we do not observe a strong global relationship between repeat expression and age, we identified HERV-K as a repeat signature associated with the aging neurotypical brain. Our study is the first global assessment of repeat expression in the neurotypical brain.

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“…The gut microbiota in animals is influenced by a multitude of factors, including environmental exposures [1,2], dietary fluctuations [3,4], age-related dynamics [5,6], sexspecific influences [7,8], and underlying genetic distinctions [9,10]. Host genetics can interact with the gut microbiota in a complex and dynamic manner, in which host genes can impact the presence/absence and quantities of microbes [11], shaping the environment for microbial survival [12], and in turn, microbes can directly or indirectly participate in the host energy metabolism and nutrient absorption [13,14], reciprocally affecting cellular functions in intricate ways through fermentation and metabolite production.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Coordinated Roles of Host Genome, Duodenal Mucosal Genes, and Microbiota in Regulating Complex Traits in Chicken

Lan,

Zhou,

et al. 2024

Preprint

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The complex interactions between host genetics and the gut microbiome are well recognized; however, the specific impact of gene expression pattern and microbial composition on each other remains to be further explored. Here we investigated this complex interplay within a sizable population of 705 hens, employing integrative analyses to examine the relationships among host genetics, mucosal gene expression, and the gut microbiota. Specific microbial taxa exhibited a strong adherence to the host genomic variants, particularly in the cecum such as the Christensenellaceae family with a heritability (h2) of 0.365. We proposed a novel concept regulatability (\({r}_{b}^{2}\)), which was derived from h2, to quantify the cumulative effects of gene expression on the given phenotypes. The duodenal mucosal transcriptome emerged as a potent influencer of duodenal microbial taxa, with exceptionally higher \({r}_{b}^{2}\) values (0.17 ± 0.01, mean ± SE) compared to h2 (0.02 ± 0.00). Through a comparative analysis of chickens and humans, we revealed similar average microbiability (m2) values of 0.18 and 0.20, and significant distinctions in average \({r}_{b}^{2}\) values (0.17 vs 0.04). Notably, cis heritability (\({h}_{cis}^{2}\)) quantifies the impact of genetic variations proximal to a gene on its expression, while trans heritability (\({h}_{trans}^{2}\)) assesses the influence of distant genetic variations. Higher \({h}_{trans}^{2}\) values compared to \({h}_{cis}^{2}\), and a greater prevalence of trans-regulated genes over cis-regulated ones underscored the significant role of loci outside the cis-window in shaping gene expression levels. Furthermore, our exploration into the regulation of duodenal mucosal genes and microbiota on 18 complex traits enhanced our understanding of their regulatory mechanism, in which gene CHST14 and its regulatory relationships with Lactobacillus salivarius jointly facilitated the deposition of abdominal fat. This study has enhanced our understanding of host-microbe dynamics, which helps to devise strategies to modulate host-microbe interactions for improving economic traits in chicken.

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Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Cited by 4 publications

References 39 publications

DNA methylation meta-analysis confirms the division of the genome into two functional groups

DNA methylation meta-analysis confirms the division of the genome into two functional groups

Lifespan analysis of repeat expression reveals age-dependent upregulation of HERV-K in the neurotypical human brain

Deciphering the Coordinated Roles of Host Genome, Duodenal Mucosal Genes, and Microbiota in Regulating Complex Traits in Chicken

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