Biology subjects

Chaitankar, V.

Publications and source records attributed to Chaitankar, V..

4 recordsLinked to original sources

bioRxiv2022

Remodeling of Il4-Il13-Il5 locus underlies selective gene expression

The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a tandem multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites, promoting tissue repair as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. We took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13 and Il5 loci were aligned in proximity whereas Il4 locus was insulated. In Th2 cells, Il4 and Il13 positioned in proximity while the Il5 locus remained distal. Select REs were separately deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.

immunology↗

bioRxiv2019

NRL- and CRX-guided gene network modulates photoreceptor presynapse size and positioning during retinal development

Unique morphologies of rod and cone photoreceptor presynaptic terminals permit the formation of synapses onto interneurons during retina development. We integrated multiple \"omics\" datasets of developing rod and S-cone-like photoreceptors and identified 719 genes that are regulated by NRL and CRX, critical transcriptional regulators of rod differentiation, as candidates for controlling presynapse morphology. In vivo knockdown of 72 candidate genes in the developing retina uncovered 26 genes that alter size and/or positioning of rod spherules in the outer plexiform layer. Co-expression of seven cDNAs with their cognate shRNAs rescued the rod presynapse phenotype. Loss of function of four genes in germline or by an AAV-mediated CRISPR/Cas9 strategy validated RNAi screen findings. A protein interaction network analysis of the 26 positive effectors revealed additional candidates in the NRL/CRX-regulated presynapse morphology-associated gene network. Follow-up knockdowns of two novel candidates support the proposed network. Our studies demonstrate a requirement of multiple components in a modular network for rod presynapse morphogenesis and provide a functional genomic framework for deciphering genetic determinants of morphological specification during development.\n\nAuthor SummaryThe relationship between neuronal morphology and function has been recognized for over 100 years. However, we still have poor understanding of genes and proteins that control morphogenesis of a specific neuron. In the current study, we address this connection between gene expression and neural morphology by identifying and knocking down a subset of expressed genes in rod photoreceptors. We ascertained a number of candidate genes controlling photoreceptor pre-synaptic terminal morphology, which is necessary for its connection with second-order neurons in the retinal circuit. Furthermore, we have curated a more plausible network of genes, either identified in our study or predicted, that are enriched for processes underlying photoreceptor morphogenesis. We suggest that our work will provide a framework for dissecting genetic basis of neuronal architecture and assist in better design of cell replacement therapies for retinal degeneration.

neuroscience↗

bioRxiv2019

lncRNAKB: A comprehensive knowledgebase of long non-coding RNAs

We have assembled a comprehensive long non-coding RNA knowledgebase (lncRNAKB) of 77,199 annotated human lncRNAs (224,286 transcripts) by methodically integrating widely used lncRNAs resources. To facilitate functional characterization of lncRNAs, we employed Genotype-Tissue Expression (GTEx) project to provide tissue-specific gene expression profiles of lncRNAs in 31 solid organ tissues. Additional information includes network analysis to identify co-expressed gene modules to potentially delineate lncRNA function. Tissue-specificity, phylogenetic conservation scores and coding potential for lncRNAs are included. Finally, using whole genome sequencing data from GTEx, expression quantitative trait loci (cis-eQTL) regulated lncRNAs were calculated in all tissues. lncRNAKB is available at http://www.lncrnakb.org.

bioinformatics↗

bioRxiv2019

Electron transport chain biogenesis activated by a JNK-insulin-Myc relay primes mitochondrial inheritance in Drosophila

Oogenesis features an enormous increase in mitochondrial mass and mtDNA copy number, which are required to furnish mature eggs with adequate mitochondria and to curb the transmission of deleterious mtDNA variants. Quiescent in dividing germ cells, mtDNA replication initiates upon oocyte determination in the Drosophila ovary, which necessitates active mitochondrial respiration. However, the underlying mechanism for this dynamic regulation remains unclear. Here, we show that an feedforward insulin-Myc loop promotes mitochondrial respiration and biogenesis by boosting the expression of electron transport chain subunits and factors essential for mtDNA replication and expression, and mitochondrial protein import. We further reveal that transient activation of JNK enhances the expression of insulin receptor and initiates the insulin-Myc signaling loop. Importantly, this signaling relay ensures sufficient mtDNA in eggs and limits the transmission of a deleterious mtDNA mutation. Our study demonstrates cellular mechanisms that couple mitochondrial biogenesis and inheritance with oocyte development.

developmental biology↗