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

Naaila Tamkeen,Romana Ishrat,Suliman Yousef Alomar,Anam Farooqui,Safia Tazyeen,Saeed Awad M Alqahtani,Nadeem Ahmad,Abdullah Al-Jurayyan

doi:10.3389/fgene.2021.597983

Naaila Tamkeen, Romana Ishrat + Show 6 more

Open Access

https://doi.org/10.3389/fgene.2021.597983

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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.

Highlights

The vigorous efforts of researchers and an increase in research techniques have paved the way for discoveries in the study of polygenic and other complex human diseases
To construct the Spina Bifida (SB) Protein-Protein Interaction (PPI) network, the candidate genes of SB listed in Table 1, were fed into STRING as seed genes. 116 of our seed genes got incorporated in the constructed primary network composed of 1,116 nodes and 40,886 edges, leaving TRPM6, which failed to make its way into the network
The data points of all the topological parameters are found to fit power law when plotted against the degree k of the SB network (First row labeled as Level “0” in Figures 1A, 2A, 3A)

Summary

Introduction

The vigorous efforts of researchers and an increase in research techniques have paved the way for discoveries in the study of polygenic and other complex human diseases. There remain a large fraction of genetic diseases with their molecular basis unknown, Spina bifida (SB) being one of them. SB, a spinal cord malformation, falls into the category of Neural Tube Defects (NTDs). This birth defect occurs when the neural tube of an embryo fails to close completely during the 4th week of pregnancy. Myelomeningocele (MMC) is the most common and serious type of SB and is often used interchangeably with it

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