Biology subjects

Panda, S.

Publications and source records attributed to Panda, S..

59 records · Page 4Linked to original sources

bioRxiv2020

A Genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms

The regulatory mechanisms of circadian rhythms have been studied primarily at the level of the transcription-translation feedback loops of protein coding genes. Regulatory modules involving non-coding RNAs are less thoroughly understood. In particular, emerging evidence has revealed the important role of miRNAs in maintaining the robustness of the circadian system. To identify miRNAs that have the potential to modulate circadian rhythms, we conducted a genome-wide miRNA screen using U2OS luciferase reporter cells. Among 989 miRNAs in the library, 120 changed the period length in a dosage-dependent manner. We further validated the circadian regulatory function of a miRNA cluster, miR-183/96/182, both in vitro and in vivo. We found that all three members of this miRNA cluster can modulate circadian rhythms. Particularly, miR-96 directly targeted a core circadian clock gene, PER2. The knockout of the miR-183/96/182 cluster in mice showed tissue-specific effects on circadian parameters and altered circadian rhythms at the behavioral level. This study identified a large number of miRNAs, including the miR-183/96/182 cluster, as circadian modulators. We provide a resource for further understanding the role of miRNAs in the circadian network and highlight the importance of miRNAs as a novel genome-wide layer of circadian clock regulation. Significance StatementAlthough miRNAs are emerging as important regulators of diverse physiological and pathological processes, our knowledge of their potential role in regulation of circadian rhythms is still limited. We deployed a cell-based genome-wide screening approach, and successfully identified mature miRNAs as cell-autonomous circadian modulators. We then specifically focused on the miR-183/96/182 cluster among the candidate miRNA hits and revealed their circadian function both in vitro and in vivo from the unbiased screen. This study provides resources for further understanding the role of miRNAs in the circadian network. It also highlights the importance of miRNAs as a novel genome-wide layer of circadian clock regulation.

molecular biology↗

bioRxiv2020

Genome-wide SNP data unravel the ancestry and signatures of divergent selection in Ghurrah pigs of India

The evolution and domestication of pigs is a complex and ongoing process. Despite its rich biodiversity and proximity to the geographical origins of Sus scrofa domesticus, the place of Indian pigs in the global phylogeny is unclear. Using microarray-derived (porcine 60K SNP chip) genotypes of 11 Ghurrah pigs from North-Western India and a public dataset comprising 2113 pigs of 146 breeds, we determined the genomic ancestry of Ghurrah pigs and compared their genetic constitution to European and Asian breeds to ascertain signatures of divergent selection. Results showed that Ghurrah pigs contain genes of Asian and European ancestry with signs of inter-species introgression. Using Admixture LD - decay statistics, the European admixture event was dated to the recent past, coinciding with the start of cross-breeding efforts in India. The complex Asian ancestry pattern of the breed resembled that of wild boars of South - Central China and Thailand, possibly suggesting introgression from an Indian wild boar relative. FST and XP - EHH comparisons with Asian breeds highlighted divergent selection in genomic regions associated with odontogenesis and skeletal muscle development. Comparisons with European commercial breeds revealed that genomic regions governing olfaction and response to sensory stimulation were under selection in Ghurrah pigs. QTL for meat and carcass traits also showed divergent selection between European breeds and Ghurrah pigs. Our results present the first genomic characterization of an Indian pig breed using dense microarray-derived genotypes and highlight the importance of further genomic characterization of Indian domestic and wild pigs.

genomics↗

bioRxiv2020

Astroglia in lateral habenula is essential for antidepressant efficacy of light

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

neuroscience↗

bioRxiv2020

Revival of light-evoked neuronal signals in the post-mortem mammalian and human retina

The retina, a highly metabolic tissue in the central nervous system, consumes the most oxygen and energy stores in the body by tissue mass/volume. Consequently, it is not surprising that retinal ischemia leads to a rapid loss of retinal light responses and electrical transmission. In this study, we show that despite a swift decline of retinal light responses after circulatory death (decay time constant {tau} = [~]1-2 min), we were able to restore mouse rod and cone photoreceptor light signals from enucleated eyes up to 3 h postmortem with significantly better postmortem recovery of cone versus rod light responses. We also demonstrate that both rod and cone phototransduction are more resistant to postmortem enucleation delay than synaptic transmission to second order neurons (bipolar cells). Encouraged by these analyses and the lack of previously successful postmortem retinal light recordings from human foveal/macular photoreceptors, we attempted to restore light responses in the human macula using donor eyes harvested 0.5 - 5 hours postmortem. Here we show successful recordings of human macular cone photoresponses in samples obtained from eyes enucleated up to 5 hours postmortem. Comparing freshly enucleated non-human primate eyes with human eyes enucleated and reoxygenated at different times after death, we show the exponential decay of the light response amplitudes has a time constant of 74 min. We find that both cause of death and donor age are useful parameters for predicting the recovery of retinal light responses in postmortem human macular tissue. Moreover, we present evidence that hypoxia and secondary acidosis, two modifiable factors, are primary contributors to the rapid loss of retinal light signaling after death. Finally, we show postmortem hypoxia rather than acidosis is the major cause of irreversible decay of the light response amplitudes. The criteria and methodology that we have established here for reviving electrical photoresponses in the postmortem human eye will serve as a new starting point for studying neurophysiology and disease in the human retina.

neuroscience↗

bioRxiv2018

The innate immune DNA sensor cGAS is a negative regulator of DNA repair hence promotes genome instability and cell death

Stringent regulation of DNA repair is essential for organismal integrity, but the mechanisms are not fully understood. Cyclic cGMP-AMP synthase (cGAS), the DNA sensor that alerts the innate immune system to the presence of foreign or damaged self-DNA in the cytoplasm is critical for the outcome of infections, inflammatory diseases and cancer. Besides this cytoplasmic function as an innate immune sensor, whether cGAS fulfills other biological roles remains unknown. Here we report that cGAS has a distinct role in the nucleus: it inhibits homologous recombination DNA repair (HR) thereby promoting genome instability and associated micronuclear generation and mitotic death. We show that cGAS-mediated inhibition of HR requires its DNA binding and oligomerization but not its catalytic activity or the downstream innate immune signaling events. Mechanistically, we show that cGAS impede RAD51-mediated DNA strand invasion, a key step in HR. These results uncover a new function of cGAS relevant for understanding its involvement in genome instability- associated disorders.

cell biology↗