Landscape of Hopx expression in cells of the immune system

Bourque, Jessica; Opejin, Adeleye; Surnov, Alexey; Iberg, Courtney A.; Gross, Cindy; Jain, Rajan; Epstein, Jonathan A.; Hawiger, Daniel

doi:10.1016/j.heliyon.2021.e08311

Cited by 5 publications

(4 citation statements)

References 53 publications

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“…The impact of damage to HOPX in the process of myocarditis development can result in signi cant alterations to the cardiac genetic architecture. HOPX, a transcriptional regulator with a role in the developmental biology of various tissues, including the heart, faces potential consequences that extend to downstream genes, transcription factors (TFs), and signaling pathways, ultimately shifting them towards a pathologic state [111]. HOPX's role in regulating the expression of genes involved in cardiogenesis suggests that damage to HOPX may lead to the dysregulation of these cardiogenic genes, disrupting the coordinated expression necessary for proper cardiac development.…”

Section: Impact Of This Damage On Switching Downstream Genes Transcri...mentioning

confidence: 99%

“…Increased expression of pro-in ammatory genes and impaired cardiomyocyte maturation, coupled with the activation of apoptotic pathways, emphasize the diverse effects that damaged HOPX can have on the heart. Understanding these emerging alterations provides valuable insights into the molecular consequences of HOPX damage, ultimately highlighting the importance of therapeutic interventions aimed at preserving its normal function and mitigating the in ammatory changes for maintaining normal cardiac genetic architecture and preventing the progression of cardiac diseases associated with myocarditis-induced damage to HOPX [111,112].…”

Section: Impact Of This Damage On Switching Downstream Genes Transcri...mentioning

confidence: 99%

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Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Shafi,

Khan,

Virk

2024

Preprint

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Background: Myocarditis-induced inflammation disrupts the intricate genetic architecture governing cardiomyocyte development and function. Understanding the specific disruptions in key regulators, such as Isl1, Nkx2–5, GATA4, and signaling pathways like Wnt and BMPs, is crucial for unraveling the molecular underpinnings of cardiac dysfunction. This investigation holds paramount importance in informing targeted therapeutic strategies to mitigate inflammation-induced genetic disruptions, offering potential breakthroughs in the management of myocarditis and improving outcomes for affected individuals. Methods: Databases, including PubMed, MEDLINE, and Google Scholar, were searched for published articles without any date restrictions, focusing on cardiac genes, signaling pathways, and transcription factors, with an emphasis on NF-κB in myocarditis. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study reveals profound disruptions in the genetic architecture of cardiomyocytes. Transcriptional regulatory networks crucial for cardiomyocyte differentiation, including Isl1, Nkx2–5, GATA4, and Tbx5, exhibit altered expression patterns, suggesting compromised maturation processes. The Brg1/Baf60 – Smarcd3 complex, HAND1/2, and MYOCD, essential for cardiogenic regulation, are susceptible to inflammatory damage, impacting cell fate determination. NF-κB-mediated damage to BMPs and the Wnt-signaling pathway results in downstream shifts, affecting gene expression dynamics. These disruptions, coupled with compromised survival mechanisms and heightened apoptotic susceptibility, contribute to cardiac dysfunction and increased arrhythmogenic risk. Altered ECM remodeling and fibrosis further underscore the complexity of myocarditis-induced genetic alterations. Insights from these results hold implications for developing targeted therapeutic strategies aimed at mitigating inflammation-induced genetic disruptions and preserving cardiac health in the context of myocarditis. Conclusion: Myocarditis-induced inflammation disrupts the intricate genetic architecture of cardiomyocytes, compromising key regulators like Isl1, Brg1/Baf60 complex, Nkx2–5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt signaling, Notch, FGF, and BMPs. This disruption leads to impaired cardiomyocyte differentiation, compromised survival mechanisms, dysregulated ECM remodeling, and heightened pro-inflammatory responses, collectively resulting in cardiac dysfunction and structural abnormalities. Targeted therapeutic interventions to mitigate inflammation-induced genetic disruptions are crucial for preserving optimal cardiac function in the challenging landscape of myocarditis.

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Section: Impact Of This Damage On Switching Downstream Genes Transcri...mentioning

confidence: 99%

Section: Impact Of This Damage On Switching Downstream Genes Transcri...mentioning

confidence: 99%

Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Shafi,

Khan,

Virk

2024

Preprint

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“…Conversely, CD45+ cells from the brain exhibited enriched T cell gene signatures. These included higher expression of transcripts associated with the T cell receptor α constant gene (TRAC), genes involved in TCR signaling (TAOK3, Sos1) (17) (18), genes regulating T cell metabolism (ERN1 and TXNIP (19), and genes linked to effector and central memory T cell programs (HSP70, DNAJB1, HSPH1, GZMA, NKG7, ID2, HELIOS (encoded by IKZF2), homeobox only protein (HOPX), and IL-7R (20) (21) (22). Additionally, the expression of the trafficking factor ITGβ2 suggested LFA-1 mediated T cell migration across the blood-brain barrier.…”

Section: Single-cell Transcriptomic Analysis Of Cd45+ Leukocytes Iden...mentioning

confidence: 99%

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain

Elizaldi,

Hawes,

Verma

et al. 2023

Preprint

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CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside other CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4 T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL57 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4 T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4 T cells in CNS immune surveillance and their decline during chronic SIV-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes.

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“…This induction promotes DC-mediated T cell unresponsiveness ( 14 ). Furthermore, HOPX has been found to modulate Treg responsiveness in autoimmune animal models ( 15 ). During COVID-19 infection, there is notable clonal expansion of CD8 + T cells in the lungs of patients and these expanded T cells exhibit high expression of HOPX ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Homeodomain-only protein suppresses proliferation and contributes to differentiation- and age-related reduced CD8+ T cell expansion

Yang,

Patrick,

et al. 2024

Front. Immunol.

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T cell activation is a tightly controlled process involving both positive and negative regulators. The precise mechanisms governing the negative regulators in T cell proliferation remain incompletely understood. Here, we report that homeodomain-only protein (HOPX), a homeodomain-containing protein, and its most abundant isoform HOPXb, negatively regulate activation-induced proliferation of human T cells. We found that HOPX expression progressively increased from naïve (TN) to central memory (TCM) to effector memory (TEM) cells, with a notable upregulation following in vitro stimulation. Overexpression of HOPXb leads to a reduction in TN cell proliferation while HOPX knockdown promotes proliferation of TN and TEM cells. Furthermore, we demonstrated that HOPX binds to promoters and exerts repressive effects on the expression of MYC and NR4A1, two positive regulators known to promote T cell proliferation. Importantly, our findings suggest aging is associated with increased HOPX expression, and that knockdown of HOPX enhances the proliferation of CD8+ T cells in older adults. Our findings provide compelling evidence that HOPX serves as a negative regulator of T cell activation and plays a pivotal role in T cell differentiation and in age-related-reduction in T cell proliferation.

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Landscape of Hopx expression in cells of the immune system

Cited by 5 publications

References 53 publications

Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain

Homeodomain-only protein suppresses proliferation and contributes to differentiation- and age-related reduced CD8+ T cell expansion

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