Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Downes, Damien J.; Cross, Amy; Hua, Peng; Roberts, Nigel; Schweßinger, Ron; Cutler, Antony J.; Munis, Altar M.; Brown, Jill M.; Mielczarek, Olga; Andrea, Carlos de; Melero, Ignacio; Gill, Deborah R.; Hyde, Stephen C.; Knight, Julian C.; Todd, John A.; Sansom, Stephen N.; Issa, Fadi; Davies, James O. J.; Hughes, Jim R.

doi:10.1038/s41588-021-00955-3

Cited by 127 publications

(130 citation statements)

References 115 publications

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“…The strong expression of CEBPB in lung tissue supports the biological relevance of this new motif ( 64) and chromatin immunoprecipitation supported by sequencing (ChIP-seq) of CEBPB in lung broblast cells of IMR-90 and HeLa, A549 alveolar basal epithelial adenocarcinoma (65). Moreover, deepHaem predicted that rs17713054-A would resulted in induced binding of CEBPB in A549 cells and IMR-90 (29) . This study found that rs17713054is an active enhancer of LZTFL1 in lungs and associated with increased risk of COVID-19 and is not in an active enhancer in immune cells, where CCR9 is expressed.…”

Section: Introductionmentioning

confidence: 65%

“…A recent study by Oxford University scientists was published in Nature genetic ( Nat Genet 53, 1606-1615 (2021). https://doi.org/10.1038/s41588-021-00955-3) showed that leucine zipper transcription factorlike 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was signi cantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31 (29). LZTFL1 is widely expressed in pulmonary epithelial cells, including ciliated epithelial cells, which have been identi ed as one of the main cellular targets for SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

“…The 3p21.31-related risk is most likely caused by pulmonary epithelial cells undergoing EMT, rather than immune cells, according to this study. LZTFL1 could be a therapeutic target because the 3p21.31 effect is conferred by a gain-of-function (29). LZTFL1 variants that induce risk of severe COVID-19 disease is not found in immune cells as in this study they rst examined open chromatin from 24 diverse immune cell populations (including T, B, natural killer and dendritic cells) in resting and stimulated states but did not identify any of the 28 severe COVID-19associated variants of LZTFL1 at 3p21.31 in open chromatin making it unlikely that a cis-regulatory mechanism in these immune cell types is responsible for COVID-19 risk.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

Elkazzaz

Abo-Amer²,

Ahmed³

et al. 2021

Preprint

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Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A

show abstract

Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

Elkazzaz

Abo-Amer²,

Ahmed³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…A recent study by Oxford University scientists was published in Nature genetic ( Nat Genet 53, 1606-1615 (2021). https://doi.org/10.1038/s41588-021-00955-3) showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was signi cantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31 (29). LZTFL1 is widely expressed in pulmonary epithelial cells, including ciliated epithelial cells, which have been identi ed as one of the main cellular targets for SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

“…The 3p21.31-related risk is most likely caused by pulmonary epithelial cells undergoing EMT, rather than immune cells, according to this study. LZTFL1 could be a therapeutic target because the 3p21.31 effect is conferred by a gain-of-function (29). LZTFL1 variants that induce risk of severe COVID-19 disease is not found in immune cells as in this study they rst examined open chromatin from 24 diverse immune cell populations (including T, B, natural killer and dendritic cells) in resting and stimulated states but did not identify any of the 28 severe COVID-19-associated variants of LZTFL1 at 3p21.31 in open chromatin making it unlikely that a cis-regulatory mechanism in these immune cell types is responsible for COVID-19 risk.…”

Section: Introductionmentioning

confidence: 99%

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to improve and boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with hematologic malignancies???. A double edged sword

Elkazzaz

Abo-Amer²,

Ahmed³

et al. 2021

Preprint

View full text Add to dashboard Cite

The COVID-19 pandemic caused by SARS-CoV-2 has become a global health crisis. Patients with haematological malignancies (blood cancers) as B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. In addition to impaired COVID-19 viral evolution and clearance was commonly seen in patients with haematological malignancies. Moreover, in patients with haematological malignancies, Covid-19 is associated with a mortality rate of 33-37%. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. After receiving COVID-19 vaccination, about one out of every four patients with blood cancer fails to produce detectable antibodies. Many studies have suggested that patients with haematological malignancies who have been fully vaccinated can develop severe and often fatal complications. COVID-19 is a virus that causes disease. A recent study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31. LZTFL1 gene is widely up regulated in respiratory epithelial cells, including ciliated epithelial cells, which have been found as one of the main cellular targets for COVID-19. The scientists in this study used a combined multiomics and machine learning approach and identified that the gain-of-function risk A allele of an SNP, rs17713054G>A, was a causative variant. With gene-expression analysis and chromosome conformation capture oxford scientists showed that the rs17713054-affected enhancer induces the interacting gene, LZTFL1. The rs17713054 A risk allele causes increased transcription by enhancing an epithelial–endothelial–fibroblast enhancer, which is aided by the addition of a second CEBPB binding motif. The risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer, according to sequence analysis.. As a result, the rs17713054 risk allele must generate a CCAAT/enhancer binding protein beta motif in order to increase covidm-19 risk by interacting with LZTFL1, according to this study. This study discovered that rs17713054 is an active enhancer of LZTFL1 in the lungs, which is linked to an increased risk of COVID-19, but not in immune cells, where CCR9 is expressed.. According to this study, LZTFL1 variants that increase the risk of severe COVID-19 disease are not found in immune cells. Here, we propose attestable hypothesis that the casual gene(LZTFL1) induced by all trans retinoic acid could be enhance the immune response in vaccinated patients with haematological malignancies SARS-CoV-2 mRNA vaccines have been shown to induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63. Fortunately, LZTFL1 has been discovered to potentially activate CD4 T cells and induce their immune response, as well as enhance IL-5 production under the control of all trans retinoic acid (ATRA). LZTFL1 expression is induced by ATRA in human primary CD4+ T cells. LZTFL1 has been found to be downregulated in a variety of cancers. TNM (tumour (T), node (N), and metastasis (M) stages of the tumour, as well as the number of metastasized lymph nodes, were found to have significant inverse correlations with loss of LZTFL1 expression (mLN). The T cell activation signal was further enhanced by overexpression of LZTFL1 in CD4+ T cells, as evidenced by increased NFAT activity. Furthermore, knocking down LZTFL1 reduced Th2 cytokine production, particularly IL-5 mRNA and protein, and suppressed ATRA-induced IL-5 production. In addition, retinoic acid is required for T cell migration in vitro and in vivo. Furthermore, trans retinoic acid was discovered to potentially downregulate EBP (CCAAT/enhancer binding protein beta motif) in the lungs, which could be used by the active enhancer rs17713054 of LZTFL1. Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A

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Understanding fundamental principles of enhancer biology at a model locus

et al. 2023

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Despite ever‐increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage‐specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co‐factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a ‘transcriptional hub’ containing a high concentration of TFs and co‐factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α‐globin gene cluster during erythropoiesis, as a model.

show abstract

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Cited by 127 publications

References 115 publications

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to improve and boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with hematologic malignancies???. A double edged sword

Understanding fundamental principles of enhancer biology at a model locus

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