DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice

McGrath‐Morrow, Sharon A.; Ndeh, Roland; Helmin, Kathryn A.; Chen, Shang-Yang; Anekalla, Kishore R.; Abdala‐Valencia, Hiam; D’Alessio, Franco R.; Collaco, Joseph M.; Singer, Benjamin D.

doi:10.1074/jbc.ra118.003589

Cited by 46 publications

(61 citation statements)

References 45 publications

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“…Measurement and analysis of DNA methylation was performed as previously described (McGrath-Morrow et al, 2018;Singer, 2019;Walter et al, 2018;Wang et al, 2018;Weinberg et al, 2019). Briefly, genomic DNA was isolated from sorted macrophage populations (Qiagen AllPrep Micro kit).…”

Section: Modified Reduced Representation Bisulfite Sequencingmentioning

confidence: 99%

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

McQuattie‐Pimentel¹,

Ren²,

Joshi³

et al. 2019

Preprint

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A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines the phenotype of long-lived alveolar macrophages during aging. While tissue-resident alveolar macrophages persist in the lung without input from monocytes over the lifespan, severe lung injury results in their replacement with monocyte-derived alveolar macrophages. These monocyte-derived alveolar macrophages are also shaped by the microenvironment both during aging and in response to a subsequent environmental challenge to become transcriptionally and functionally similar to tissue-resident alveolar macrophages. These findings show that changes in alveolar macrophage phenotypes during injury and aging are not cell autonomous but instead are shaped by changes in the aging lung microenvironment.

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Section: Modified Reduced Representation Bisulfite Sequencingmentioning

confidence: 99%

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

McQuattie‐Pimentel¹,

Ren²,

Joshi³

et al. 2019

Preprint

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“…Supernatant was discarded and the colon was washed twice with HBSS, cut into 2-mm pieces, placed in 10 mL of pre-warmed RPMI + 10% FBS Flow cytometry analysis and fluorescence-activated cell sorting. Single-cell suspensions of visceral organs and blood were prepared and stained for flow cytometry analysis and fluorescence-activated cell sorting as previously described (20,46,(53)(54)(55) using the reagents and cytometer setup shown in Supplemental Table 1. Cell counts of single-cell suspensions were obtained using a hemocytometer with trypan blue exclusion or a Cellometer with AO/PI staining (Nexcelom Bioscience) before preparation for flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

“…Annexin staining. Single-cell suspensions were incubated with a UV-excitable viability dye (Molecular Probes #L23105) followed by surface staining as above and previously described (20,46,53,54). Cells were then washed and resuspended in annexin-binding buffer (10 mM HEPES, 140 mM NaCl, and 2.4 mM CaCl2; pH 7.4) at a concentration of 1 x 10 6 cells/mL.…”

Section: Discussionmentioning

confidence: 99%

“…Counts data for uniquely mapped reads over exons were obtained using SeqMonk v1.45.4 and filtered to protein-coding genes and genes with at least 1 count per million in at least 2 samples. Differential gene expression analysis was performed with the edgeR v3.24.3 R/Bioconductor package using R v3.5.1 and RStudio v1.1.447 as stated in the text and individual figure legends and as described previously (54,57). K-means clustering and heat maps were generated using the Morpheus web interface (https://software.broadinstitute.org/morpheus/).…”

Section: Discussionmentioning

confidence: 99%

“…Modified reduced representation bisulfite sequencing. Genomic DNA was subjected to mRRBS as previously described (46,54,(59)(60)(61)(62). Bisulfite conversion efficiency averaged 99.52% ± 0.052% (SD) as estimated by the measured frequency of unmethylated CpGs in λ-bacteriophage DNA (New England BioLabs, #N3013S) added at a 1:200 mass ratio to each sample.…”

Section: Discussionmentioning

confidence: 99%

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Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin¹,

Morales‐Nebreda²,

Acosta³

et al. 2020

Preprint

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Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3 + cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

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Bronchopulmonary dysplasia as a determinant of respiratory outcomes in adult life

Collaco¹,

McGrath‐Morrow

2021

Pediatric Pulmonology

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Respiratory disease is unfortunately common in preterm infants with the archetype being bronchopulmonary dysplasia (BPD). BPD affects approximately 50,000 preterm infants in the U.S. annually with substantial morbidity and mortality related to its pathology (alveolar, airway, and pulmonary vasculature maldevelopment). Predicting the likelihood and severity of chronic respiratory disease in these children as they age is difficult and compounded by the lack of consistent phenotyping. Barriers to understanding the actual scope of this problem include few longitudinal studies, information limited by small retrospective studies and the ever‐changing landscape of therapies in the NICU that affect long‐term respiratory outcomes. Thus, the true burden of adult respiratory disease caused by premature birth is currently unknown. Nevertheless, limited data suggest that a substantial percentage of children with a history of BPD have long‐term respiratory symptoms and persistent airflow obstruction associated with altered lung function trajectories into adult life. Small airway disease with variable bronchodilator responsiveness, is the most common manifestation of lung dysfunction in adults with a history of BPD. The etiology of this is unclear however, developmental dysanapsis may underlie the airflow obstruction in some adults with a history of BPD. This type of flow limitation resembles that of aging adults with chronic obstructive lung disease with no history of smoking. It is also unclear whether lung function abnormalities in people with a history of BPD are static or if these individuals with BPD have a more accelerated decline in lung function as they age compared to controls. While some of the more significant mediators of lung function, such as tobacco smoke and respiratory infections have been identified, more work is necessary to identify the best means of preserving lung function for individuals born prematurely throughout their lifespan.

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DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice

Cited by 46 publications

References 45 publications

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Bronchopulmonary dysplasia as a determinant of respiratory outcomes in adult life

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