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Publications

Enhancer deregulation in TET2 Mutant Clonal Hematopoiesis is associated with increased COVID-19 related inflammation severity and mortality


Moritz Binder, Terra L. Lasho, Wazim Mohammed Ismail, Nana A. Ben-Crentsil, Jenna A. Fernandez, Minsuk Kim, Susan M. Geyer, Amelia Mazzone, Christy M. Finke, Abhishek A. Mangaonkar, Jeong-Heon Lee, Kwan Hyun Kim, Vernadette A. Simon, Fariborz Rakhshan Rohakthar, Amik Munankarmy, Susan M. Schwager, Jonathan J. Harington, Melissa R. Snyder, Nathalie M. Droin, Eric Solary, Keith D. Robertson, Eric D. Wieben, Eric Padron, Nicholas Chia, Alexandre Gaspar-Maia, Mrinal M. Patnaik
BioRxiv Aug 2022
Abstract

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 downregulation 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.

VIEW

Area

COVID-19

Institution Type

Academia

Indication / Modality

COVID-19

Goal of Study

CHIP, Clinical Profiling

Key Genes

TET2, DNMT3A, CBL, SRSF2, ZRSR2

PAD Project

No

Analytes Assessed

Extracellular Protein, InDels, SNV

Sample Storage

Fresh Frozen

Sample Prep

Whole Cells

Sample Type

PBMC

Species

Human

Panel Used

Myeloid Catalog Panel

Proof Point Demonstrated

Cell Identity, Multi-omics, Co-occurrence
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