Multiomics single timepoint measurements to predict severe COVID-19 – Authors' reply

Garapati, Kishore; Byeon, Seul Kee; Walsh, Jesse R; Jenkinson, Garrett; Cattaneo, Roberto; O’Horo, John C.; Badley, Andrew D.; Pandey, Akhilesh

doi:10.1016/s2589-7500(22)00250-3

Cited by 3 publications

(1 citation statement)

References 5 publications

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“…We used Olink Explore 1536 panel assay (Olink Proteomics [Uppsala, Sweden]), which uses proximity extension assay technology coupled to a readout methodology based on next generation sequencing (Illumina NovaSeq 6000, NextSeq 550, and NextSeq 2000; all manufactured by Illumina; appendix 1 p 2), to quantify protein targets, as previously described. 62…”

Section: Methodsmentioning

confidence: 99%

Single cell multiomic analyses reveal divergent effects ofDNMT3AandTET2mutant clonal hematopoiesis in inflammatory response

Binder

Lasho

Ismail

et al. 2022

Preprint

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Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which factors determine severity of illness and long-term outcomes. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. We show that mutations in the gene coding for the methylcytosine dioxygenase TET2 promotes amplification of classical and intermediate monocyte subsets. Using single cell multiomic sequencing approaches, we identify cell-specific gene expression changes associated with the loss of TET2 and significant epigenomic deregulation affecting enhancer accessibility of a subset of transcription factors involved in monocyte differentiation. We further identify EGR1 down-regulation secondary to TET2-mediated hypermethylation, resulting in overexpression of MALAT1, a lncRNA that plays a role in hematopoietic stem cell differentiation and monocyte lineage commitment. Together, these data provide a mechanistic insight to the poor prognostic value of clonal hematopoiesis in patients infected with Sars-COV2.

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Section: Methodsmentioning

confidence: 99%

Single cell multiomic analyses reveal divergent effects ofDNMT3AandTET2mutant clonal hematopoiesis in inflammatory response

Binder

Lasho

Ismail

et al. 2022

Preprint

Self Cite

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Single cell multiomic analyses reveal divergent effects of DNMT3A and TET2 mutant clonal hematopoiesis in inflammatory response

Mohammed,

Fernandez,

Binder

et al. 2024

Preprint

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Background DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposing epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematological neoplasms. While individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Results Here we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant CH on COVID-19-related cytokine release severity and mortality. Using single cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid cells. Using single cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of IL32, a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Conclusions We demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19 related inflammatory morbidity and mortality. DNMT3Amt CH involves myeloid and lymphoid cells and in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can serve as a potential biomarker for adverse inflammatory outcomes.

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Senescence Signatures Predict Hospitalization Risk and Severity in COVID-19 Patients

Singh Rai,

Lynch,

McLarnon

et al. 2024

AgingBio

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Multiomics single timepoint measurements to predict severe COVID-19 – Authors' reply

Cited by 3 publications

References 5 publications

Single cell multiomic analyses reveal divergent effects ofDNMT3AandTET2mutant clonal hematopoiesis in inflammatory response

Single cell multiomic analyses reveal divergent effects ofDNMT3AandTET2mutant clonal hematopoiesis in inflammatory response

Single cell multiomic analyses reveal divergent effects of DNMT3A and TET2 mutant clonal hematopoiesis in inflammatory response

Senescence Signatures Predict Hospitalization Risk and Severity in COVID-19 Patients

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