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Advancements in the field of epigenetics in Asthma and COPD on children’s airways and blood cells
Abstract:
Asthma is an issue around the world that is becoming more prevalent. Asthma and Chronic obstructive pulmonary disease (COPD) are both respiratory system chronic inflammatory diseases. It narrows the airway, swells, and produces mucus, causing major breathing issues.
Asthma can be a life-threatening condition. The severity of the condition may vary depending on age, gender, and race. Not only are these factors involved, but also some external stressors such as pollution, microbes, and behaviors (smoking) might develop worsen conditions. Epigenetics is strongly linked to asthma and Chronic obstructive pulmonary diseases, and it broadens its horizons. Several research on the asthma-COPD overlap and epigenome-wide meta-analyses have recently been published. Various studies have sought to establish tissue and cell-specific DNA methylation in asthmatic patients, which controls airway remodeling and other lung functions. These investigations revealed fresh information about the pathophysiology of asthma and COPD, along with novel CpG sites and biomarkers.
More research and investigation with the most up-to-date techniques are needed to discover the etiology of asthma and COPD development, novel genes, CpG sites, biomarkers, and treatments to minimize asthma and COPD severity.
Keyword:
Epigenetics, Asthma, COPD, Nasal epithelium, DNA methylation, Inflammation, Gene, Promoter, Biomarker, Smoking
Background:
British biologist Konrad Waddington first coined the term “epigenetics” in the mid-20th century. The concept called epigenetic landscape was introduced to explain complicated tissues and organs of an organism originally arising from undifferentiated cells and the way in which cell fate is determined during development (Jaenisch et al., 2003). Epigenetics is defined as the reversible control of gene expression that occurs irrespective of nucleotide sequence and is mediated primarily by DNA methylation (DNAm), histone modifications, and non-coding RNA (Durham et al., 2011). Epigenetics is also known as a chemical alteration without changing the gene and controlling the expression level of the sequence. In epigenetics, various Epigenome-wide Association Study (EWAS) revealed and recent research has focused on influence among the external and internal conditions. Then epigenetic extend our consciousness to new environmental causes and tackle diseases.

Asthma refers to a disease of chronic airway inflammation that affects nearly 262 million individuals and 461000 deaths in 2019 worldwide (Vos et al., 2019). Asthma is a heterogeneous inflammatory airways disease that affects people of different ages. Asthma prevalence in children between the ages 0–17 years was 8 to 10 percent on average between 2001 and 2013 (Akinbami et al., 2016). Asthma can be triggered by different factors including environmental risk factors and epigenetic modification (Bégin et al., 2014). COPD is another most common medical condition, affecting more than 10% of persons over the age of 65 globally (Boudewijn et al., 2017). The development of COPD could be both genetic and environmental causes, although some genetic variants, like alpha-1 antitrypsin shortage, and environmental triggers, including smoking cigarettes or secondhand smoking, quite well cause for COPD (Kokelj et al., 2021), the underlying molecular pathways of the condition currently unknown. Based on the molecular characteristics, the genome-wide genetic analysis provides chances to acquire fresh insights into the causes of COPD (Boudewijn et al., 2017).
Since roughly 2016, various researchers have investigated epigenetic changes linked to asthma, with a particular focus on DNAm, histone modification, non-coding RNAs, interpretation to clinical applications, body fluid hypersecretion, and pre-birth maternal openness to tobacco. The genome-wide association study (GWAS) showed us that epigenetics has a great impact to develop asthma in people. It reveals that age is highly related to asthma significance also race and gender contribute some evidence of significance (Ntontsi et al., 2021). Many functions of immune cells associated with asthma, notably T lymphocytes other blood cells are regulated by epigenetic markers (Bégin et al., 2014). Whole blood or peripheral blood mononuclear cells (PBMCs), airway, nasal, or bronchial epithelium cells provided the majority of the data on DNA methylation in asthma. In this review, the focus would be DNAm markers within AA siblings, novel cytosine guanine dinucleotide (CpG) sites, genes in the epithelium and blood cells. I will further discuss some age and sex-related links with asthma and the overlap between asthma and COPD.
DNA methylation in Epithelium and Blood cells
DNA (Deoxyribonucleic acid) is a chemically based sequence of nucleotide (A, T, C, G) bases. The 80% human genome is packed into nucleosomes and situated in chromosomes with 3D designs. Every genetic material is bundled into a chromosome ten thousand times thinner than its expanded length during mitosis. Nucleosomes are typically formed by densely coiling (Figure A) DNA surrounding histone proteins, that are then compacted to generate chromatin, a highly complex mixture of DNA, RNA, and polypeptide that constitutes chromosomes (Roach, 2011). In nucleosomes, the fundamental parts are histone proteins, and their distinctive post-translational modifications (PTMs) are occurring like acetylation, methylation, phosphorylation. The airway epithelium is crucial in asthma because it initiates and modulates immune responses to a variety of infections. The epithelium of the respiratory tract plays a significant role. It works with asthma to trigger and control a refractory response to various types of pathogenic microorganisms and environmental factors (Watson et al., 2015). Nowadays Covid19 is a dominating and terrific disease. Previous research finds out that DNAm is also associated with viruses namely the Human papillomavirus (HPVs) (Clarke et al., 2018), Epstein-Barr virus (EBVs) (Lam et al., 2019), and Human rhinovirus (HRVs) (Pech et al., 2018). DNAm was responsible for the activation of three genes called HLA-B, IRF3, and MX1. These three genes have been associated with the pathogenesis of SARS-CoV-2 infection (Rathod et al., 2021). So, people who suffer from asthma might have severe conditions if they are affected by SARS-CoV-2 (Rathod et al., 2021).
Epigenetic changes are caused by environmental influences. Exposure may alter germline epigenetic, and it lasts from generation to generation. DNAm was the first epigenetic phenomenon discovered and is also the most discussed. (Jirtle et al., 2007). The enzymes that make up the group known as DNA methyltransferases (DNMTs) catalyze the transfer of a methyl group to the 5 positions of the cytosine pyrimidine (C) ring of a CpG site (Bégin et al., 2014). CpG sites are important for their palindromic nature. It assures that each methylation type is replicated throughout the cellular division (Zhang et al., 2010). The precise DNA demethylation mechanism in different genes is not yet fully understood. Proteins of the methyl-cytosine dioxygenase family with ten-eleven translocation (TET) mediate DNA demethylation (Somineni et al., 2016). Methylation of CpG sites interferes with the binding of transcription factors and recruitment of methyl-binding proteins, initiating chromatin densification and gene silencing. It occurs primarily in clusters called “CpG” islands and is most common around gene promoters that are generally not methylated. In epigenetic studies more concentration is given to DNAm on the CpG islands as this is linked with suppression of gene expression and chromatin remodeling within the promoter gene (Jaenisch et al., 2003). DNA methylation is usually associated with quality suppression (Potaczek et al., 2017 and Alhamwe et al., 2020).

Figure A: Chromosome and Epigenetic Modifications (Smith and mill, 2011).
A nucleosome is generated when DNA is coiled with histones. DNAm at CpG islands and covalent alterations to histone tails change the physical shape of the genomes, attract methyl (-CH3) binding proteins as well as allow transcription factors that can access the genetic material. DNAm around CpG dinucleotides potentially interferes with transcription by inhibiting some transcription regulators binding sites (Smith and mill, 2011).
Nasal epithelial cells (NECs) are much more susceptible to alterations as a result of environmental stimuli because of their location. Whereas the nasal epithelium was found to be a suitable surrogate for the respiratory epithelium, NECs had greater DNA methylation connected with asthma versus airway epithelia (Hudon et al., 2019). The expression levels in the nasal epithelium are altered because of smoking (Zhang et al., 2010).
The ESS (Exposure Sibling Study) reported an association between DNAm and asthma. The researcher identified six CpG sites linked with childhood asthma (Zhang et al., 2018). CpG-rich regions typically present in the regulatory sections of DNA, and methylation of GC-rich sites in these regulatory areas causes the expression of genes to drop (De Vries et al., 2018). Among the six CpG sites, three of them are previously reported, such as cg14007090 is situated at intron of LAMA5 (Nguyen et al., 2005; Saotome et al., 2003), cg20223677 is situated at the promoter of DEF104A/DEFB104B (Lehrer, 2011), and cg26017880 is situated at ATP9B promoter (Takatsu et al., 2011) but the other three (Table 1) are novel sites. Furthermore, cg23602092 was associated with the frequency of asthma symptoms in asthmatic patients and located in the TET1 promoter region. (McConnell et al., 2010).

Table 1: The Exposure Sibling Study linked between nasal DNA methylation and childhood asthma.
The associations were significant for these three sites, and it is verified by pyrosequencing. Though ICAC study showed only one highly significant value (cg00112952, p = 0.005) and another moderate significant value (cg23602092).

CpG

Gene

ESS 450 K (n = 58)
ICAC 450 K (n = 72)
P-value

References
p-value
(No SV)
p-value
(With SV)
cg00112952
OR2B11
0.004
0.004
0.005
Zhang et al (2018)
cg23602092
TET1
0.016
0.011
0.034
Zhang et al (2018)
cg14830002
OR2B11
0.001
0.002
0.092
Zhang et al (2018)

The promoter region of TET1 and OR2B11 both located in the transcription downstream end site called NLRP3, also includes a protein in the NALP3 inflammasome complex (McConnell et al., 2010). The NALP3 plays a significant role in inflammation control, regulation, cell recruitment, and programmed cell death (Besnard et al., 2011). Moreover, recently it is reported that NLRP3 regulates transcription of Th2 differentiation (Bruchard et al., 2015). The link between asthma-related DNA methylation and exposures, allergies, and asthma symptoms was investigated. One of them (cg14830002) is associated with asthma and allergies but the other two (cg23602092 and cg00112952) are not associated with allergy (Zhang et al., 2018). The overall expression of OR2B11, NLRP3, and TET1, genes situated near cg00112952, cg14830002, and cg23602092, was changed when DNA methylation has been reduced. Finally, Zhang et al (2018) conclude those three novel CpG sites and DNAm levels that are associated with childhood asthma. The study had some limitations for this reason we need to do more study to evaluate the result, data and investigate more interactions of genes and CpG sites, gene expression, and histone modification mechanism. A qPCR analysis finds that in TET1 promoter DNA hypomethylation develops asthma in African American children (McConnell et al., 2010). Several studies report about traffic-related air pollution (TRAP) significantly express the gene and proteins related to asthma.
This is the first time, researchers discovered that an array of CpG-sites connected with respiratory function levels in whole blood are also linked to tobacco smoking within target tissue (De Vries et al., 2018). On the other hand, another study showed never smoked people had DNAm associated with lung functions (De Vries et al., 2019). It also indicates that investigation into epigenetics, asthma, and COPD is critical, so more work would have to be done by researchers.
Asthma biomarker, Epigenome-wide association study, and Asthma COPD overlap
As previously stated, my focus will be on different epithelium cells and blood cells then the EWAS and asthma-COPD overlap. The choosing of objects for DNA samples was among the most difficult aspects of DNAm studies on asthma. There is little direct access towards the DNA of lung tissue, which would be predominantly implicated in asthma pathogenesis (Michels et al., 2013). The easiest and simple method is to use the surrogate tissues for diagnosis (Poole et al., 2014). For diagnostic accuracy, AEC (Airway epithelial cell) and NEC were better biomarkers than PBMC (Lin et al., 2020). Further studies and DNAm formatting in tissues or cells will increase the discovery of novel DNAm, biomarkers, and drug targets (Lin et al., 2020). As DNAm is usually highly tissued or cell-type-specific (Yang et al., 2012; Armstrong et al., 2014), PBMC-based methylation patterns may not correlate with AEC-based airway epithelial cell methylation patterns (Brugha et al., 2017). Alterations in DNAm in animal (mouse) models have been shown to be associated with T-cell-specific expression of cytokines and disease progression. They discovered that CD69 and CD28, which are involved in T cell activation in allergic inflammation, were upregulated. (Miki-Hosokawa et al., 2009; Kimzey et al., 2004). There are some additional variables that protect against Th1 cell responses, such as the passive transmission of maternal antibodies through breastfeeding as well as some early infections (Noutsios et al., 2014; Xu et al., 2014). Epigenetics has become more well-identified as a vital connection among inherited genome alterations and environmental stressors such as tobacco smoking (Madrigano et al., 2011).
Numerous genetic variations linked to asthmatic have been discovered in large-scale GWAS, many of which are unique to childhood asthma (Moffatt et al., 2010). For a better understanding of asthma, COPD, or asthma-COPD overlap (ACO) we need to perform more EWAS or meta-analysis. As far as the two largest EWAS studies are concerned, they have been finished and it added a new perspective of research. The recent (meta-analysis) one was 631 cases and 2231 controls (Reese et al., 2019), and another was 247 cases and 2949 controls (Xu et al., 2018) using nine and six different cohorts. Reese et al (2019) found 179 methylated CpGs and 36 regions associated with asthma and Xu et al (2018) Found 27 methylated CpG sites but only 14 passed the significance value. These 14 asthma-related CpG sites on DNAm have been linked to asthma in children between ages 4-16 years (Xu et al., 2018).
Asthmatics are frequently omitted from COPD research, therefore knowledge of the disease’s etiology and relevant therapies for ACO is limited (Woodruff et al., 2017). One study showed that COPD and asthma had symptoms of hay fever compared with only COPD patients (Celli et al., 2004). Additionally, they showed that gender and smoking had not had any significant role in asthma and COPD. On the other hand, they found race-specific links to asthma and COPD. Despite significant limitations in the research, they were able to show that people with COPD and asthma had different and clinically relevant traits (Hardin et al., 2011).
Conclusion
In allergy and asthma research, epigenetics is a fascinating new field. The existence of asthma could be effectively determined from the nasal epithelium. Differences in DNAm have been linked to asthma in youngsters, according to studies. Though there has been remarkable progress in asthma COPD study in recent times, there are still many unanswered concerns in asthma-COPD for which epigenetics study may provide a solution. Even though there are still various problems in terms of obtaining data, determining which tissues and cells are most suited for research, and deciding the right approach to overcome the limitations. Ultimately, making the greatest use of data and technology has the potential to improve people’s lives and even lifespan.

List of Abbreviations
ACO – Asthma-COPD overlap
AEC – Airway epithelial cell
ATP9B – ATPase Phospholipid Transporting 9B (Putative)
COPD – Chronic obstructive pulmonary diseases
DNAm – DNA methylation
DNMTs – DNA methyltransferases
ESS – Exposure Sibling Study
EBV – Epstein-Barr virus
HPV – Human papillomavirus
HRV – Human rhinovirus
ICAC – Inner City Asthma Consortium
IRF3 – Interferon regulatory factor 3
LAMA5 – Laminin Subunit Alpha 5
NECs – Nasal epithelial cells
OR2B11 – Olfactory Receptor Family 2 Subfamily B Member 11
PBMC – peripheral blood mononuclear cells
PTMs – Post-Translational Modifications
qPCR – Quantitative polymerase chain reaction
SV – Surrogate variable
TRAP – Traffic-related air pollution
TET1 – Ten-Eleven Translocation 1
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-S M Jahid Mostofa
Msc at bioinformatics
Teesside University, Middleborough, England