Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders

Abstract

Background Hemoglobin is a tetramer consisting of two α-chains and two β-chains of globin. Hereditary aberrations in the synthesis of one of the globin chains are at the root of thalassemia, one of the most prevalent monogenic diseases worldwide. In humans, in addition to α- and β-globins, embryonic zeta-globin and fetal γ-globin are expressed. Immediately after birth, the expression of fetal Aγ- and Gγ-globin ceases, and then adult β-globin is mostly expressed. It has been shown that in addition to erythroid cells, hemoglobin is widely expressed in nonerythroid cells including neurons of the cortex, hippocampus, and cerebellum in rodents; embryonic and adult brain neurons in mice; and mesencephalic dopaminergic brain cells in humans, mice, and rats. Lately, there is growing evidence that different forms of anemia (changes in the number and quality of blood cells) may be involved in (or may accompany) the pathogenesis of various cognitive and mental disorders, such as Alzheimer’s and Parkinson’s diseases, depression of various severity levels, bipolar disorders, and schizophrenia. Higher hemoglobin concentrations in the blood may lead to hyperviscosity, hypovolemia, and lung diseases, which may cause brain hypoxia and anomalies of brain function, which may also result in cognitive deficits. Methods In this study, a search for unannotated single-nucleotide polymorphisms (SNPs) of erythroid genes was initially performed using our previously created and published SNP-TATA_Z-tester, which is a Web service for computational analysis of a given SNP for in silico estimation of its influence on the affinity of TATA-binding protein (TBP) for TATA and TATA-like sequences. The obtained predictions were finally verified in vitro by an electrophoretic mobility shift assay (EMSA). Results On the basis of these experimental in vitro results and literature data, we studied TATA box SNPs influencing both human erythropoiesis and cognitive abilities. For instance, TBP–TATA affinity in the HbZ promoter decreases 6.6-fold as a result of a substitution in the TATA box (rs113180943), thereby possibly disrupting stage-dependent events of “switching” of hemoglobin genes and thus causing erythroblastosis. Therefore, rs113180943 may be a candidate marker of severe hemoglobinopathies with comorbid cognitive and mental disorders associated with cerebral blood flow disturbances. Conclusions The literature data and experimental and computations results suggest that the uncovered candidate SNP markers of erythropoiesis anomalies may also be studied in cohorts of patients with cognitive and/or mental disorders with comorbid erythropoiesis diseases in comparison to conventionally healthy volunteers. Research into the regulatory mechanisms by which the identified SNP markers contribute to the development of hemoglobinopathies and of the associated cognitive deficits will allow physicians not only to take timely and adequate measures against hemoglobinopathies but also to implement strategies preventing cognitive and mental disorders.

An experimental study of the effects of SNPs in the TATA boxes of the <i>GRIN1, ASCL3</i> and <i>NOS1</i> genes on interactions with the TATA-binding protein

“…Previously, using Web service SNP_TATA_Comparator (Ponomarenko M. et al, 2015) and in vitro experiments, we studied effects of SNPs in TATA boxes within core promoters of human genes to predict potential SNP markers, for example, markers of obesity (Arkova et al, 2015), autoimmune diseases (Ponomarenko M. et al, 2016), Alzheimer's disease (Ponomarenko P. et al, 2017), aggressiveness (Chadaeva et al, 2016), circadian rhythm disorders , anomalies of female reproductive potential (Chadaeva et al, 2018), erythropoiesis disorders (Sharypova et al, 2018), and resistance to anticancer therapy (Turnaev et al, 2016). Then, on the basis of our results and literature data, we made findings suggesting that SNPs that disrupt erythropoiesis are likely to be associated with cognitive and neuropsychiatric disorders in humans (Ponomarenko M. et al, 2020).…”

Plant_SNP_TATA_Z-Tester: A Web Service That Unequivocally Estimates the Impact of Proximal Promoter Mutations on Plant Gene Expression

“…Within Tikhonov’s regularization [ 61 ], this correlation ( Figure 2 a) characterizes a similarity between the ill-posed inverse problem of evaluating the transcriptional outcome of mutations in plant proximal promoters ( Figure 1 ) and the analogous well-posed problem for humans, which has already been solved using our public Web service Human_SNP_TATA_Z-tester [ 28 ] (see in-depth description in the Supplementary Materials [ 18 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ]). With this in mind, Figure 2 depicts how we adapted it step-by-step for comparing between wildtype and mutant variants of the plant promoter DNA sequences under study in their effects on gene expression, i.e., our new Web service Plant_SNP_TATA_Z-tester created in this work.…”

“…We processed DNA sequences by means of our public Web service Plant_SNP_TATA_Z-tester (e.g., Figure 3 a and Figure 6 ) created in this work, as depicted in Figure 2 . To this end, as its prototype, we used our previously developed Web service Human_SNP_TATA_Z-tester [ 28 ] (see description [ 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ] in the Supplementary Materials ), and we expanded it only with Equation (2) in line with Tikhonov’s regularization [ 61 ].…”

“…It uses a step-by-step approximation [ 29 ]: (i) TBP slides along DNA [ 18 ]; (ii) TBP stops at the best TBP-binding site [ 30 , 31 ]; (iii) the TBP–promoter complex is fixed by the DNA bending at a right angle [ 32 ], as proven experimentally [ 33 ]. Subsequently, using Human_SNP_TATA_Z-tester, we analyzed 15243 SNPs, which yielded 3229 candidate SNP markers aggravating or relieving the development of human disorders, such as subfertility [ 28 , 34 ], obesity [ 35 ], hypertension [ 36 ], cognitive disorders [ 37 ], atherosclerosis [ 38 ], Alzheimer’s disease [ 39 , 40 ], hematopoietic disorders [ 41 ], and many others (for a review, see [ 42 ]). Lastly, from article to article, we selectively experimentally verified these predictions, as did some independent researchers (e.g., see [ 43 ]).…”

Bioinformatics search for genetic markers of socially significant diseases in promoters of human genes

“…Results: It allows to estimate how SNPs effect on the TATA-binding protein (TBP) binding affinity for the 70 bp proximal promoters in front of transcription start sites (TSS) of the human genes within our three-step model of TBP-promoter interaction [2] taking into account both nucleotide context and conformational together with physicochemical features of the B-helical double-stranded DNA [3]. Due to this we examined 15243 SNPs in question that yielded 3229 candidate SNP-markers aggravating or relieving the development of human diseases such as obesity [4], autoimmune disorders [5], subfertility [6], atherosclerosis [7], rheumatoid arthritis [8], hypertension [9], Alzheimer's disease [10], mental disorders [11] as well as SNP-markers of resistance to anticancer chemotherapy were also identified [12]. Conclusion: An independent selective experimental control verification [13,14] shown a significant linear correlation between the in silico-estimated and in vitro-measured values of the TBP-promoter affinity rates (r = 0.77; p < 0.000001).…”