Insights from Chromosome-Centric Mapping of Disease-Associated Genes: Chromosome 12 Perspective

Abstract

In line with the aims of the Chromosome-based Human Proteome Project and the Biology/Disease-based Human Proteome Project, we have been studying differentially expressed transcripts and proteins in gliomas—the most prevalent primary brain tumors. Here, we present a perspective on important insights from this analysis in terms of their co-expression, co-regulation/de-regulation, and co-localization on chromosome 12 (Chr. 12). We observe the following: (1) Over-expression of genes mapping onto amplicon regions of chromosomes may be considered as a biological validation of mass spectrometry data. (2) Their co-localization further suggests common determinants of co-expression and co-regulation of these clusters. (3) Co-localization of "missing" protein genes of Chr. 12 in close proximity to functionally related genes may help in predicting their functions. (4) Further, integrating differentially expressed gene-protein sets and their ontologies with medical terms associated with clinical phenotypes in a chromosome-centric manner reveals a network of genes, diseases, and pathways—a diseasome network. Thus, chromosomal mapping of disease data sets can help uncover important regulatory and functional links that may offer new insights for biomarker development.

Microsomal membrane proteome of low grade diffuse astrocytomas: Differentially expressed proteins and candidate surveillance biomarkers

“…Changes at the chromosome levels such as mutations, copy number variations are important factors that may affect downstream events relevant to tumor development. We also mapped differentially expressed proteins to the chromosome 12 which is implicated in glial tumors 23 , and found that three of the over expressed proteins, CNPY2, MYL6, LIMA1, mapped to the regions on the chromosome that have been described as amplicons 24 25 . This provides a rationale and biological basis for their overexpression and confirms mass spectrometry results.…”

Transcriptomic and Proteomic Data Integration and Two-Dimensional Molecular Maps with Regulatory and Functional Linkages: Application to Cell Proliferation and Invasion Networks in Glioblastoma

“…The proliferation networks consist of cell cycle kinases, CDK4 and CDK6 and their downstream signalling molecules involving CHI3L1, RAC2 and PLG. CDK4 is also the most frequently amplified gene that is part of the chromosome 12q13-15 amplification cluster in gliomas and concordantly associated with high protein and transcript levels implying its important role in glioma malignant progression 23,29,30 . Matrix metalloproteinases, MMP9 and cathepsin B participate in tumor cell proliferation, angiogenesis and invasion and inhibiting both was found to result in the reduction of tumor cell growth and invasion 31 .…”

“…CDK4 is also the most frequently amplified gene that is part of the chromosome 12q13-15 amplification cluster in gliomas and concordantly associated with high protein and transcript levels, implying its important role in glioma malignant progression. 23,29,30 Matrix metalloproteinases MMP9 and cathepsin B participate in tumor cell proliferation, angiogenesis, and invasion, and inhibiting both was found to result in the reduction of tumor cell growth and invasion. 31 All these molecules are overexpressed in both proteomic and transcriptomic data, leading to increased cell cycle progression and cell survival.…”

Recent Advances in the Chromosome-Centric Human Proteome Project: Missing Proteins in the Spot Light

“…The Chromosome 12 Consortium from India and South Asia has focused on differentially expressed transcripts and proteins in gliomas and their coexpression, coregulation, and colocalization on chromosome 12. Overexpression of genes maps onto amplicon regions; colocalization suggests common determinants of coexpression and coregulation; close proximity to functionally related genes may help predict their functions; and integration of gene–protein sets with ontologies of medical terms can reveal the disease network (Jayaram et al).…”