Browsing by Author "Ramakrishnan, Aarthi"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Human protein-RNA interaction network is highly stable across mammals
    (BMC, 2019-12-30) Ramakrishnan, Aarthi; Janga, Sarath Chandra; Medical and Molecular Genetics, School of Medicine
    Background RNA-binding proteins (RBPs) are crucial in modulating RNA metabolism in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Although previous studies on the conservation of RBP targets have been carried out in lower eukaryotes such as yeast, relatively little is known about the extent of conservation of the binding sites of RBPs across mammalian species. Results In this study, we employ CLIP-seq datasets for 60 human RBPs and demonstrate that most binding sites for a third of these RBPs are conserved in at least 50% of the studied vertebrate species. Across the studied RBPs, binding sites were found to exhibit a median conservation of 58%, ~ 20% higher than random genomic locations, suggesting a significantly higher preservation of RBP-RNA interaction networks across vertebrates. RBP binding sites were highly conserved across primates with weak conservation profiles in birds and fishes. We also note that phylogenetic relationship between members of an RBP family does not explain the extent of conservation of their binding sites across species. Multivariate analysis to uncover features contributing to differences in the extents of conservation of binding sites across RBPs revealed RBP expression level and number of post-transcriptional targets to be the most prominent factors. Examination of the location of binding sites at the gene level confirmed that binding sites occurring on the 3′ region of a gene are highly conserved across species with 90% of the RBPs exhibiting a significantly higher conservation of binding sites in 3′ regions of a gene than those occurring in the 5′. Gene set enrichment analysis on the extent of conservation of binding sites to identify significantly associated human phenotypes revealed an enrichment for multiple developmental abnormalities. Conclusions Our results suggest that binding sites of human RBPs are highly conserved across primates with weak conservation profiles in lower vertebrates and evolutionary relationship between members of an RBP family does not explain the extent of conservation of their binding sites. Expression level and number of targets of an RBP are important factors contributing to the differences in the extent of conservation of binding sites. RBP binding sites on 3′ ends of a gene are the most conserved across species. Phenotypic analysis on the extent of conservation of binding sites revealed the importance of lineage-specific developmental events in post-transcriptional regulatory network evolution.
  • Thumbnail Image
    Item
    Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
    (Springer Nature, 2022-10-26) Fulton, Sasha L.; Wenderski, Wendy; Lepack, Ashley E.; Eagle, Andrew L.; Fanutza, Tomas; Bastle, Ryan M.; Ramakrishnan, Aarthi; Hays, Emma C.; Neal, Arianna; Bendl, Jaroslav; Farrelly, Lorna A.; Al-Kachak, Amni; Lyu, Yang; Cetin, Bulent; Chan, Jennifer C.; Tran, Tina N.; Neve, Rachael L.; Roper, Randall J.; Brennand, Kristen J.; Roussos, Panos; Schimenti, John C.; Friedman, Allyson K.; Shen, Li; Blitzer, Robert D.; Robison, Alfred J.; Crabtree, Gerald R.; Maze, Ian; Biology, School of Science
    With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.