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1.
EBioMedicine ; 106: 105251, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39024897

RESUMO

BACKGROUND: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. METHODS: In this single centre prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing. PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. FINDINGS: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harbouring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life. INTERPRETATION: Blood DNA methylation levels identify PASC, stratify PASC severity, and suggest that DNA motifs are targeted by circadian rhythm-regulating pathways in PASC. FUNDING: This project has been funded by the following agencies: NIH-AI173035 (A. Jaitovich and R. Alisch); and NIH-AG066179 (R. Alisch).


Assuntos
COVID-19 , Metilação de DNA , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/sangue , COVID-19/virologia , Feminino , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , Estudos Prospectivos , Adulto , Idoso , Síndrome de COVID-19 Pós-Aguda , Aprendizado de Máquina , Sequenciamento Completo do Genoma , Biomarcadores/sangue , Qualidade de Vida , Betacoronavirus/genética
2.
Epigenetics ; 19(1): 2380930, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39066680

RESUMO

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways.


Assuntos
Axônios , Metilação de DNA , Ácido Fólico , Espermatozoides , Ácido Fólico/farmacologia , Ácido Fólico/administração & dosagem , Animais , Masculino , Camundongos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Axônios/metabolismo , Axônios/efeitos dos fármacos , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Ilhas de CpG , Feminino , Regeneração Nervosa/efeitos dos fármacos , Epigênese Genética , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/citologia
3.
Proc Natl Acad Sci U S A ; 121(3): e2317668121, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38194455

RESUMO

Orofacial clefts of the lip and palate are widely recognized to result from complex gene-environment interactions, but inadequate understanding of environmental risk factors has stymied development of prevention strategies. We interrogated the role of DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression of the key DNA methyltransferase enzyme DNMT1 was detected throughout palate morphogenesis in the epithelium and underlying cranial neural crest cell (cNCC) mesenchyme, a highly proliferative multipotent stem cell population that forms orofacial connective tissue. Genetic and pharmacologic manipulations of DNMT activity were then applied to define the tissue- and timing-dependent requirement of DNA methylation in orofacial development. cNCC-specific Dnmt1 inactivation targeting initial palate outgrowth resulted in OFCs, while later targeting during palatal shelf elevation and elongation did not. Conditional Dnmt1 deletion reduced cNCC proliferation and subsequent differentiation trajectory, resulting in attenuated outgrowth of the palatal shelves and altered development of cNCC-derived skeletal elements. Finally, we found that the cellular mechanisms of cleft pathogenesis observed in vivo can be recapitulated by pharmacologically reducing DNA methylation in multipotent cNCCs cultured in vitro. These findings demonstrate that DNA methylation is a crucial epigenetic regulator of cNCC biology, define a critical period of development in which its disruption directly causes OFCs, and provide opportunities to identify environmental influences that contribute to OFC risk.


Assuntos
Fenda Labial , Fissura Palatina , Animais , Camundongos , Fenda Labial/genética , Metilação de DNA , Fissura Palatina/genética , Crista Neural , Metilases de Modificação do DNA , Proliferação de Células
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