TY - JOUR T1 - Evolutionarily conserved network properties of intrinsically disordered proteins. JF - PLoS One Y1 - 2015 A1 - Rangarajan, Nivedita A1 - Kulkarni, Prakash A1 - Hannenhalli, Sridhar KW - Animals KW - Cluster Analysis KW - Databases, Protein KW - Drosophila KW - Drosophila Proteins KW - Evolution, Molecular KW - HUMANS KW - Intrinsically Disordered Proteins KW - Metabolic Networks and Pathways KW - Mice KW - Osmotic Pressure KW - Protein Interaction Maps KW - Saccharomyces cerevisiae KW - Saccharomyces cerevisiae Proteins AB -

BACKGROUND: Intrinsically disordered proteins (IDPs) lack a stable tertiary structure in isolation. Remarkably, however, a substantial portion of IDPs undergo disorder-to-order transitions upon binding to their cognate partners. Structural flexibility and binding plasticity enable IDPs to interact with a broad range of partners. However, the broader network properties that could provide additional insights into the functional role of IDPs are not known.

RESULTS: Here, we report the first comprehensive survey of network properties of IDP-induced sub-networks in multiple species from yeast to human. Our results show that IDPs exhibit greater-than-expected modularity and are connected to the rest of the protein interaction network (PIN) via proteins that exhibit the highest betweenness centrality and connect to fewer-than-expected IDP communities, suggesting that they form critical communication links from IDP modules to the rest of the PIN. Moreover, we found that IDPs are enriched at the top level of regulatory hierarchy.

CONCLUSION: Overall, our analyses reveal coherent and remarkably conserved IDP-centric network properties, namely, modularity in IDP-induced network and a layer of critical nodes connecting IDPs with the rest of the PIN.

VL - 10 CP - 5 M3 - 10.1371/journal.pone.0126729 ER - TY - JOUR T1 - Derepression of Cancer/testis antigens in cancer is associated with distinct patterns of DNA hypomethylation JF - BMC CancerBMC CancerBMC Cancer Y1 - 2013 A1 - Kim, R. A1 - Kulkarni, P. A1 - Sridhar Hannenhalli KW - *DNA Methylation KW - *Gene Expression Regulation, Neoplastic KW - *Genes, X-Linked KW - Antigens, Neoplasm/*genetics KW - Binding Sites KW - Cluster Analysis KW - CpG Islands KW - Gene Expression Profiling KW - HUMANS KW - Male KW - Neoplasms/*genetics/*metabolism KW - Promoter Regions, Genetic KW - Protein Binding KW - Protein Interaction Domains and Motifs KW - Testis/*metabolism AB - BACKGROUND: The Cancer/Testis Antigens (CTAs) are a heterogeneous group of proteins whose expression is typically restricted to the testis. However, they are aberrantly expressed in most cancers that have been examined to date. Broadly speaking, the CTAs can be divided into two groups: the CTX antigens that are encoded by the X-linked genes and the non-X CT antigens that are encoded by the autosomes. Unlike the non-X CTAs, the CTX antigens form clusters of closely related gene families and their expression is frequently associated with advanced disease with poorer prognosis. Regardless however, the mechanism(s) underlying their selective derepression and stage-specific expression in cancer remain poorly understood, although promoter DNA demethylation is believed to be the major driver. METHODS: Here, we report a systematic analysis of DNA methylation profiling data from various tissue types to elucidate the mechanism underlying the derepression of the CTAs in cancer. We analyzed the methylation profiles of 501 samples including sperm, several cancer types, and their corresponding normal somatic tissue types. RESULTS: We found strong evidence for specific DNA hypomethylation of CTA promoters in the testis and cancer cells but not in their normal somatic counterparts. We also found that hypomethylation was clustered on the genome into domains that coincided with nuclear lamina-associated domains (LADs) and that these regions appeared to be insulated by CTCF sites. Interestingly, we did not observe any significant differences in the hypomethylation pattern between the CTAs without CpG islands and the CTAs with CpG islands in the proximal promoter. CONCLUSION: Our results corroborate that widespread DNA hypomethylation appears to be the driver in the derepression of CTA expression in cancer and furthermore, demonstrate that these hypomethylated domains are associated with the nuclear lamina-associated domains (LADS). Taken together, our results suggest that wide-spread methylation changes in cancer are linked to derepression of germ-line-specific genes that is orchestrated by the three dimensional organization of the cancer genome. VL - 13 SN - 1471-2407 (Electronic)
1471-2407 (Linking) N1 - Kim, Robert
Kulkarni, Prakash
Hannenhalli, Sridhar
eng
R01 GM100335/GM/NIGMS NIH HHS/
R01GM100335/GM/NIGMS NIH HHS/
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
England
2013/03/26 06:00
BMC Cancer. 2013 Mar 22;13:144. doi: 10.1186/1471-2407-13-144. U2 - 3618251 J1 - BMC cancerBMC cancer ER -