Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism

Abstract

Introductory paragraph Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function 1 . This silencing is largely controlled by non-coding elements and their disruption might cause human disease 2 . We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 ( HK1 ). HK1 is widely expressed across all tissues except for liver and pancreatic beta-cells and is thus termed a “disallowed gene” in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta-cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.

Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming

“…These features are similar to promoter element features of housekeeping genes, tailored for their ubiquitous expression [67]. HK1 promoter also contains regulatory sites known as sp sites within the P2 BOX which are essential for promoter activity and binding of protein factors in lower vertebrates to humans [60,68,69]. The role of non-coding elements in regulating HK1 and their association with congenital hyperinsulinism has also been reported [68].…”

“…HK1 promoter also contains regulatory sites known as sp sites within the P2 BOX which are essential for promoter activity and binding of protein factors in lower vertebrates to humans [60,68,69]. The role of non-coding elements in regulating HK1 and their association with congenital hyperinsulinism has also been reported [68]. Alternative splicing forms multiple HK1 isoforms, i.e., HK1 (ubiquitous), HKR (erythrocytes), HK-TA/TB (testis-A/B), HK-TB (testis-B), and HK-TD (testis-D).…”

Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming

“…These features are similar to promoter element features of housekeeping genes, tailored for their ubiquitous expression [64]. HK1 promoter also contains regulatory sites known as sp sites within the P2 BOX, which are essential for promoter activity and the binding of protein factors in lower vertebrates to humans [57,65,66]. The role of non-coding elements in regulating HK1 and their association with congenital hyperinsulinism has also been reported [65].…”

“…HK1 promoter also contains regulatory sites known as sp sites within the P2 BOX, which are essential for promoter activity and the binding of protein factors in lower vertebrates to humans [57,65,66]. The role of non-coding elements in regulating HK1 and their association with congenital hyperinsulinism has also been reported [65]. Alternative splicing generates multiple HK1 isoforms, i.e., HK1 (ubiquitous), HKR (erythrocytes), HK-TA/TB (testis-A/B), HK-TB (testis-B), and HK-TD (testis-D).…”

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism

“…2). Recently, Wakeling et al performed whole genome sequencing on 135 individuals with genetic testing negative HI and identified non-coding variants within a regulatory region of HK1 intron 2 that co-segregated with disease in families [7 ▪▪ ]. Using epigenomic analysis, single-nuclei assay for transposase-accessible chromatine with sequencing and a high-throughput genomic and epigenomic technique, they demonstrated that these variants encompass a region of chromatin accessibility within a regulatory domain for the HK1 promoter.…”