Identification of epigenetic factor KAT2B gene variants for possible roles in congenital heart diseases

Abstract

Congenital heart disease (CHD) is a group of anatomic malformations in the heart with high morbidity and mortality. The mammalian heart is a complex organ, the formation and development of which are strictly regulated and controlled by gene regulatory networks of many signaling pathways such as TGF-β. KAT2B is an important histone acetyltransferase epigenetic factor in the TGF-β signaling pathway, and alteration in the gene is associated with the etiology of cardiovascular diseases. The aim of this work was to validate whether KAT2B variations might be associated with CHD. We sequenced the KAT2B gene for 400 Chinese Han CHD patients and evaluated SNPs rs3021408 and rs17006625. The statistical analyses and Hardy–Weinberg equilibrium tests of the CHD and control populations were conducted by the software SPSS (version 19.0) and PLINK. The experiment-wide significance threshold matrix of LD correlation for the markers and haplotype diagram of LD structure were calculated using the online software SNPSpD and Haploview software. We analyzed the heterozygous variants within the CDS region of the KAT2B genes and found that rs3021408 and rs17006625 were associated with the risk of CHD.

Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis

“…GO [76], SLC16A9 [77], ACADSB (acyl-CoA dehydrogenase short/branched chain) [78], IMPA1 [79], CD300LG [80], CIRBP (cold inducible RNA binding protein) [81], PIK3R1 [82], YEATS4 [83], USP2 [84], NEDD9 [85], CHCHD5 [86] and ERAP1 [87] promotes hypertension. HSPB1 [88], CRYAB (crystallin alpha B) [89], ANXA5 [90], CCR2 [91], RGS4 [92], TNFRSF1A [93], XBP1 [94], NKX2-5 [95], NEU1 [96], GSTP1 [97], COMT (catechol-O-methyltransferase) [98], LIMK1 [99], CAMKK1 [100], CD276 [101], SMARCA4 [102], ADORA2B [103], ACOT1 [104], RGN (regucalcin) [105], PPA2 [106], KAT2B [107], PDK1 [108], CS (citrate synthase)…”

“…GO and REACTOME pathway enrichment analyses were used to investigate the interactions of these DEGs. SARS-CoV infections [45], asparagine N-linked glycosylation [46], neutrophil degranulation [47], immune system [48], respiratory electron transport [49], metabolism [50], complex I biogenesis [51], neddylation [52], localization [53], membrane [54], protein binding [55], small molecule metabolic process [56] RGN (regucalcin) [105], PPA2 [106], KAT2B [107], PDK1 [108], CS (citrate synthase) [109], FGF12 [110], AQP4 [111], LMOD2 [112], SELENBP1 [113], MB (myoglobin) [114], S100A1 [115], RYR2 [116], GPC5 [117], JARID2 [118], EGFR (epidermal growth factor receptor) [119], FUNDC1 [120], S1PR1 [121], EPAS1 [122] and OSBPL11 [123] genes are a potential biomarkers for the detection and prognosis of HF at an early age. A previous study reported that CALR (calreticulin) [124], BSCL2 [125], PKD1 [126], TMBIM1 [127], CHST15 [128] [190], SLC2A4 [191], HLA-DOA [192], TAP2 [193], HLA-DPA1 [194], NSMCE2 [195], NDUFA4 [196], HMG20A [197], AMY2B…”

Cardiac Acetylation in Metabolic Diseases

“…Post-translational acetylation triggers modification of the activity of several proteins that occurs in obesity, diabetes and early stage of heart failure as detailed below [ 67 , 68 ]. Table 2 summarizes the cardiac modulation of KATs and KDACs expression levels reported in metabolic heart disease.…”

Epigenetics and Congenital Heart Diseases

“…T-box proteins, mutated in Holt-Oram syndrome (TBX5) and DiGeorge syndrome (TBX1), display highly conserved residues, allowing direct interaction with both histone demethylase (H3K27) and methyltransferase (H3K4): both syndromes include cardiac manifestations [ 24 ], underlining the highly regulatory nature of these pathogenic mechanisms; treatment with demethylase inhibitors of Tbx1-KO mice rescues the cardiac phenotype [ 25 ]. Histone acetyltransferase variants were shown to be associated with CHD (ventricular septal defects, atrial septal defects, patent ductus arteriosus and tetralogy of Fallot) in a Chinese Han cohort [ 26 ], perhaps hinting at a mechanism for polygenic susceptibility models. Histone modifications also have the advantage of being highly dynamic in nature and allowing time-specific regulation of gene expression: PRDM6, a methyltransferase involved in maintaining cells in an undifferentiated stage with proliferative potential is highly expressed in ductal tissue, and will drastically fall in the postnatal phase, allowing for differentiation and ductus arteriosus closure.…”