Identification of the Key Regulators of Spina Bifida Through Graph-Theoretical Approach

Abstract

Spina Bifida (SB) is a congenital spinal cord malformation. Efforts to discern the key regulators (KRs) of the SB protein-protein interaction (PPI) network are requisite for developing its successful interventions. The architecture of the SB network, constructed from 117 manually curated genes was found to self-organize into a scale-free fractal state having a weak hierarchical organization. We identified three modules/motifs consisting of ten KRs, namely, TNIP1, TNF, TRAF1, TNRC6B, KMT2C, KMT2D, NCOA3, TRDMT1, DICER1, and HDAC1. These KRs serve as the backbone of the network, they propagate signals through the different hierarchical levels of the network to conserve the network’s stability while maintaining low popularity in the network. We also observed that the SB network exhibits a rich-club organization, the formation of which is attributed to our key regulators also except for TNIP1 and TRDMT1. The KRs that were found to ally with each other and emerge in the same motif, open up a new dimension of research of studying these KRs together. Owing to the multiple etiology and mechanisms of SB, a combination of several biomarkers is expected to have higher diagnostic accuracy for SB as compared to using a single biomarker. So, if all the KRs present in a single module/motif are targetted together, they can serve as biomarkers for the diagnosis of SB. Our study puts forward some novel SB-related genes that need further experimental validation to be considered as reliable future biomarkers and therapeutic targets.

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps

“…A large group of KEs (KE IDs 277, 281, 280, 425, 958, 959, 960, 1656, and 279) related to thyroid disruption and presents a direct link with chemically-induced congenital hypothyroidism (ICD-11 5A00) (Korevaar et al, 2016;Sun et al, 2022). KE IDs 1502 and 1503 characterizing defective histone acetylation were established as key regulators of processes leading to neural tube defect cases such as spina bifida (ICD-11 LA02) and anencephaly (ICD-11 LA00) (Tamkeen et al, 2021;Takla et al, 2023). Most importantly, KE ID 381 represents the brain-derived neurotrophic factor (BDNF), a key molecule necessary for healthy brain development and notably its learning and memory function.…”