Epigenetic Causes Research Articles

Understanding environmental epigenomics in autism spectrum disorder: an interview with Farah RZahir.

In this interview, Dr Farah RZahir speaks with Storm Johnson, Commissioning Editor for Epigenomics, on her work to date in the field of epigenomics, autism and intellectual disability. Dr Farah RZahir specializes in the identification of novel genetic and epigenetic causes for neurodevelopmental diseases. Her PhD, awarded in 2011 by the University of British Columbia (UBC), resulted in the characterization of new intellectual disability (ID) syndromes, as well as discovery of several new causative genes for the disorder. She was awarded the prestigious James Miller Memorial Prize for integrating basic and clinical science in 2010. Her PhD dissertation was nominated for the Governor General's gold medal - the highest possible accolade at UBC for doctoral research work. She then completed a postdoctoral tenure in Canada's premier Michael Smith Genome Sciences Centre, where she used whole-genome-sequencing methods to comprehensively assess genetic, molecularand structural causes for ID, employing several firsts for bioinformatic data mining in the field. During her postdoctorate she won three distinguishedawards and was a fellow of the Canadian Institute of Health Research, ranking in the top 2% nationally. Dr Zahir was appointed as an Assistant Professor at the Hamad Bin Khalifa University in 2016, where she led a group focused on neurogenomics and neuroepigenomics research. She was a foundingmember of the Precision and Genomics Medicine graduate program there. Currently she has rejoined UBC's department of Medical Genetics. Among her most significant achievements is the establishment of the novel Zahir Friedman syndrome, an intellectual disability/autism spectrum disorder syndrome that is caused by a major epigenomic regulator. Her current primary research interest is how epigenomics can be changed by environmental impactsand how these effects may be harnessed for neurodevelopmental disorders' prophylaxis and therapeutics.

Epigenetic control of metastasis

Cancer Metastasis is when cancer becomes deadly. Unsuccessful searches for driver mutations of metastasis have led some to explore alternative epigenetic causes. Pierce et al. found that the protein kinase LKB1, better known for influencing cancer through regulation of metabolism, had a tumor-suppressive role in one mouse lung cancer model. This tumor develops largely because of epigenomic effects on chromatin accessibility. Loss of LKB1 activates distinct waves of epigenetic remodeling in primary and metastatic tumor cells. Metastasis was mediated by activation of the transcription factor SOX17. The authors were then able to detect a small population of cells in primary tumors with the epigenetic characteristics of later metastatic cells, revealing a promising therapeutic target. Nat. Cell Biol. 23 , 915 (2021).

MiR-378-3p Knockdown Recapitulates Many of the Features of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal neoplasms of the hematopoietic stem cell that result in aberrant differentiation of hematopoietic lineages caused by a wide range of underlying genetic, epigenetic, and other causes. Despite the myriad origins, a recognizable MDS phenotype has been associated with miRNA aberrant expression. A model of aberrant myeloid maturation that mimics MDS was generated using a stable knockdown of miR-378-3p. This model exhibited a transcriptional profile indicating aberrant maturation and function, immunophenotypic and morphologic dysplasia, and aberrant growth that characterizes MDS. Moreover, aberrant signal transduction in response to stimulation specific to the stage of myeloid maturation as indicated by CyTOF mass cytometry was similar to that found in samples from patients with MDS. The aberrant signaling, immunophenotypic changes, cellular growth, and colony formation ability seen in this myeloid model could be reversed with azacytidine, albeit without significant improvement of neutrophil function.

PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

BackgroundThe role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported.MethodsWe report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients.ResultsAll patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient’s fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients.ConclusionsWe provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18

Acquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.

Genome-wide DNA methylation and transcription analysis in tongue and biceps femoris muscles of cloned pigs with macroglossia.

Cloned animals are prone to abnormal phenotypes such as enlarged tongue, fetal oversize, and progeria. In the present study, whole-genome bisulfite sequencing and mRNA sequencing were performed on tongue and biceps femoris muscles of cloned piglets with and without macroglossia, in an attempt to elucidate the epigenetic causes of the macroglossia phenotype. We identified 14958 and 18752 differentially methylated regions in the tongue and biceps femoris muscles, respectively, of macroglossia piglets and these correspond to 4574 and 4772 differentially methylated genes compared with the control group (piglets without macroglossia). Larger methylation difference was found in tongue muscle than in biceps femoris muscle. In total, 114 genes in tongue and 72 genes in biceps femoris muscles were found to be differentially expressed between the two groups. Of these differentially expressed genes in tongue muscle, 31 were also differentially methylated genes, among which DIO3 and ZIC1 were imprinting or predicted imprinting genes. These two and another six overlapping genes (ALDH1A2, MKX, MAB21L2, CA3, RANBP3L, and MYL10) are crucial factors involved in embryonic development or tissue and organ development. GO enrichment analysis suggested possible alteration of these processes. Our study provides novel molecular insights into the formation of macroglossia in cloned pigs.

Obesity management: at the forefront against disease stigma and therapeutic inertia

Obesity is a complex chronic relapsing disease, resulting from the interaction between multiple environmental, genetic and epigenetic causes, and supported by changes in the neuroendocrine mechanisms regulating energy balance and body weight. Adipose tissue dysfunction contributes to obesity-related complications. However, the prevalent narrative about the causes and mechanisms of obesity remains a much more simplistic one, based on the false assumption that individuals can fully control their body weight through appropriate behavioural choices. According to this narrative, obesity is simply reversible “persuading” the patient to follow healthier and more virtuous individual behaviours (moral judgement). This persistent narrative forms the deep root of the stigmatisation of people with obesity at the individual level and creates a clear discrepancy on how obesity prevention and cure are designed in comparison with the case of other non-communicable chronic diseases (clinical stigma). The promotion of systemic preventive measures against obesity is not supported at a political and social level by the persistence of a narrative of obesity as the simple consequence of individual failures and lack of willpower. The simplistic narrative of obesity as a self-imposed condition with an easy way-out (“eat less and move more”) creates a clear discrepancy on how obesity is managed by health care systems in comparison with other NCDs. The over-estimation of the efficacy of therapeutic intervention solely based on patients education and lifestyle modification is responsible of therapeutic inertia in health care professionals and in clinical guidelines, limiting or delaying the adoption of more effective therapeutic strategies, like anti-obesity medications and bariatric surgery. In conclusion, the persistence of a narrative describing obesity as a self-induced easily reversible condition has profound consequences on how obesity prevention and management are build, including the design and implementation of obesity management guidelines and a tendency to therapeutic inertia.Level of evidence: No level of evidence.

The epigenetic regulation of synaptic genes contributes to the etiology of autism.

Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.

Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect.

Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals. Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR. We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: -0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients. Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects.

Recreating the Face - A Mini-Review of Current Studies on 3D Bioprinting in Oral and Maxillofacial Surgery

According to the United States National Institute of Dental and Craniofacial Research, craniofacial anomalies are the most common birth defects. Genetic, epigenetic, and environmental causes lead to craniofacial anomalies which can range from cleft lip and palate to major defects in the development of the skull, face, brain, eyes, ears, and nose. Oral and maxillofacial surgeries are performed on individuals with craniofacial defects, but success of surgery is dependent on nature of the defect.

Reproductive technologies, female infertility, and the risk of imprinting-related disorders

BackgroundEpidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility.From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013–2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed.ResultsCompared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13–1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43–2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06–1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk.ConclusionsThis prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).

A case report of congenitally abnormal rabbitheaded stillbirth Najdi lamb

The congenital head anomalies are most often used to describe defects in the eyes, mouth, nose, skull, and or brain. The faulty embryogenesis most likely found to be associated with abnormal genetic or epigenetic causes during pregnancy. Eventually it leads to congenital anomalies. Rabbit-headed Lamb (RH) is a disorder in sheep breeding that is characterized by some deformities in the head and the face. A dead –day old- crossbred white Najdi lamb with a deformed face and head was reported to be born in the current case. The external and physical examination revealed a deformed skull and facial region with a unilateral eye, fused mouth, piglike nose, and patent skull with the brain coming out from left eye orbit. Additionally, the lamb was very skinny with unusual long extremities. This is the first report of this syndrome that describes such deformities in a stillbirth Najdi breed lamb.

4355 Impact of Demographic & Racial Differences on DNA Repair Capacity in Lung Cancer

OBJECTIVES/GOALS: Lung cancer is the leading cause of cancer-related mortality in the United States for both men and women. African Americans are disproportionately affected with lung cancer, having higher incidence and mortality rates compared to Caucasian men and women. African American smokers are diagnosed with lung cancer at a lower age with lower cumulative smoking history. Differences in socioeconomic and environmental factors likely contribute to lung cancer disparities, but less is known about acquired biologic alterations that can promote initiation and progression of lung cancer, particularly in African Americans. This is of interest because there may be other biological, genetic, or environmental factors contributing to lung cancer outcomes as it relates to differences in gender and race. One potential biologic variable may be in the DNA repair capacity (DRC), which describes a cell’s ability to repair damage to DNA caused by carcinogens, oxidants, and radiation. Altered DNA repair is a hallmark of cancer, leading to mutations and malignant transformation. We hypothesize that DRC is decreased in African Americans with lung cancer compared to Caucasian Americans with lung cancer, contributing to the disparity that exists in this racial group. We will 1) perform a retrospective chart review to determine demographic differences between African Americans and Caucasians at three central Indiana hospitals and 2) determine the impact of race and lung cancer on DRC amongst African Americans and Caucasians with and without lung cancer. METHODS/STUDY POPULATION: Lung cancer patients are identified in 3 central Indiana hospitals with different payer source and patient populations using ICD codes. Collected demographics include age, gender, pack-years, lung cancer histology, treatment, and mortality. DRC is measured by host-cell reactivation (non-homologous end-joining and nucleotide excision repair pathways) by flow-cytometry. Measurement of DRC is performed on PBMCs obtained from 120 patients (male and female, African Americans and Caucasians with and without lung cancer). Correlation of DRC and lung cancer will be determined by comparing lung cancer diagnosis to quartile DRC, and adjusted for confounders (measured demographics). Correlative measures will include measures of DNA damage and genomic instability. RESULTS/ANTICIPATED RESULTS: 3450 lung cancer patients were diagnosed with lung cancer at Indiana University Hospital between 1/1/2000 – 5/31/2015. Of these, 48.2% were female and 92.7% smokers. African Americans, Caucasians and Other ethnicities represented 12%, 86% and 2%, respectively. Of smokers, 11.4% were African American. The primary payer source was Federal/Medicare. Retrospective review of lung cancer patients from two additional health systems (county and VA hospitals) will be performed as above with outcomes measured. DRC and additional correlative measures will be performed as in Methods. DISCUSSION/SIGNIFICANCE OF IMPACT: If present, altered DRC in African Americans compared to Caucasians may contribute to the disproportional impact of lung cancer on African Americans. If DRC is decreased in African Americans with lung cancer, future studies will focus on identifying potential genetic, epigenetic and environmental causes for this decrease.

Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer.

Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.

Genetic and epigenetic regulation of abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are focal dilations of the aorta that develop from degenerative changes in the media and adventitia of the vessel. Ruptured AAAs have a mortality of up to 85%, thus it is important to identify patients with AAA at increased risk for rupture who would benefit from increased surveillance and/or surgical repair. Although the exact genetic and epigenetic mechanisms regulating AAA formation are not completely understood, Mendelian cases of AAA, which result from pathologic variants in a single gene, have helped provide a basic understanding of AAA pathophysiology. More recently, genome wide associated studies (GWAS) have identified additional variants, termed single nucleotide polymorphisms, in humans that may be associated with AAAs. While some variants may be associated with AAAs and play causal roles in aneurysm pathogenesis, it should be emphasized that the majority of SNPs do not actually cause disease. In addition to GWAS, other studies have uncovered epigenetic causes of disease that regulate expression of genes known to be important in AAA pathogenesis. This review describes many of these genetic and epigenetic contributors of AAAs, which altogether provide a deeper insight into AAA pathogenesis.

Does SNORD116 mediate aspects of psychosis in Prader-Willi syndrome? Evidence from a non-clinical population

The paternally expressed gene SNORD116 encodes a set of short nucleolar RNAs that affect the expression of hundreds of other genes via epigenetic interactions. Lack of expression for SNORD116 has been implicated in major phenotypes of Prader-Willi Syndrome (PWS). Rates of psychosis and autism spectrum disorders are greatly increased in PWS, but the genetic and epigenetic causes of these increases remain unknown. We genotyped a large population of typical individuals for five SNPs within SNORD116 and phenotyped them for variation in schizotypal and autism spectrum traits. SNORD116 SNP and haplotype variation mediated variation exclusively in the Schizotypal Personality Questionnaire - Ideas of Reference subscale, which reflects variation in aspects of paranoia. The effect was restricted to females. SNORD116 represents, in addition to UBE3A and NDN-MAGEL2, a third, independent locus in the 15q11-q13 imprinted region that preferentially or exclusively affects levels of paranoia. This convergent pattern may reflect a common neural pathway affected by multiple genes, or an effect of interactions between the imprinted loci.

Genetic variability and transgenerational regulation of investment in sex in the monogonont rotifer Brachionus plicatilis

In cyclical parthenogens such as aphids, cladocerans and rotifers, the coupling between sexual reproduction and the production of resting stages (diapausing eggs) imposes strong constraints on the timing of sex. Whereas induction of sex is generally triggered by environmental cues, the response to such cues may vary across individuals according to genetic and nongenetic factors. In this study, we explored genetic and epigenetic causes of variation for the propensity for sex using a collection of strains from a Spanish population of monogonont rotifers (Brachionus plicatilis) in which variation for the threshold population density at which sex is induced (mixis threshold) had been documented previously. Our results show significant variation for the mixis threshold among 20 clones maintained under controlled conditions for 15 asexual generations. The effect of the number of clonal generations since hatching of the diapausing egg on the mixis ratio (proportion of sexual offspring produced) was tested on 4 clones with contrasted mixis thresholds. The results show a negative correlation between the mixis threshold and mixis ratio, as well as a significant effect of the number of clonal generations since fertilization, sex being repressed during the first few generations after hatching of the diapausing egg.

A novel inherited epigenetic cause of pseudohypoparathyroidism type 1b

A novel inherited epigenetic cause of pseudohypoparathyroidism type 1b

Metallopanstimulin-1 (MPS-1) mediates the promotion effect of leptin on colorectal cancer through activation of JNK/c-Jun signaling pathway

Obesity is a major epigenetic cause for colorectal cancer (CRC). Leptin is implicated in obesity-associated CRC, but the underlying mechanism remains unclear. The current study identified over-expression of metallopanstimulin-1 (MPS-1) in CRC patients through microarray and histological analysis, especially in obese CRC patients. MPS-1 was correlated with advanced tumor stage, suggesting its association with CRC progression. In addition, MPS-1 over-expression was associated with poor overall survival (OS) in obese CRC patients, but not in their non-obese counterparts, suggesting its potential as a prognostic marker of obese CRC patients. MPS-1 expression was positively associated with circulating leptin levels in CRC patients, especially in obese cases. Functional experiments demonstrated that MPS-1 silencing inhibited tumor proliferation and colony formation, and induced apoptosis of CRC cells in vitro. Converse results were obtained from the experiments with MPS-1 over-expression. Mechanistically, MPS-1 executed its action through induction of c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moreover, the promotion effect of MPS-1 on CRC progression was modulated by leptin. In vivo studies demonstrated that MPS-1 silencing suppressed tumor growth of CRC via inhibiting JNK/c-Jun signaling. Collectively, this study indicates that MPS-1 promotes leptin-induced CRC via activating JNK/c-Jun pathway. MPS-1 might represent a potent candidate for the treatment and prognostic prediction of obesity-associated CRC.

Epigenetic Priming in Immunodeficiencies.

Immunodeficiencies (IDs) are disorders of the immune system that increase susceptibility to infections and cancer, and are therefore associated with elevated morbidity and mortality. IDs can be primary (not caused by other condition or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). Most primary immunodeficiencies (PIDs) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the immune system. A large percentage of PIDs are associated with a defective development and/or function of lymphocytes and, especially, B cells, the ones in charge of generating the different types of antibodies. B-cell development is a tightly regulated process in which many different factors participate. Among the regulators of B-cell differentiation, a correct epigenetic control of cellular identity is essential for normal cell function. With the advent of next-generation sequencing (NGS) techniques, more and more alterations in different types of epigenetic regulators are being described at the root of PIDs, both in humans and in animal models. At the same time, it is becoming increasingly clear that epigenetic alterations triggered by the exposure to environmental agents have a key role in the development of secondary immunodeficiencies (SIDs). Due to their largely reversible nature, epigenetic modifications are quickly becoming key therapeutic targets in other diseases where their contribution has been known for more time, like cancer. Here, we establish a parallelism between IDs and the nowadays accepted role of epigenetics in cancer initiation and progression, and propose that epigenetics forms a “third axis” (together with genetics and external agents) to be considered in the etiology of IDs, and linking PIDs and SIDs at the molecular level. We therefore postulate that IDs arise due to a variable contribution of (i) genetic, (ii) environmental, and (iii) epigenetic causes, which in fact form a continuum landscape of all possible combinations of these factors. Additionally, this implies the possibility of a fully epigenetically triggered mechanism for some IDs. This concept would have important prophylactic and translational implications, and would also imply a more blurred frontier between primary and secondary immunodeficiencies.