Biology subjects

Maganti, R.

Publications and source records attributed to Maganti, R..

3 recordsLinked to original sources

bioRxiv2020

Sleep and Diurnal Rest-Activity Rhythm Disturbances in a Mouse Model of Alzheimer's Disease

Study ObjectivesAccumulating evidence suggests a strong association between sleep, amyloid-beta (A{beta}) deposition, and Alzheimers disease (AD). We sought to determine if: (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) A{beta} levels are responsive to treatment with mGluR5 inhibitors. MethodsDiurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography (EEG), while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and A{beta} levels measured in brain lysates. ResultsJ20 mice exhibited a 4.5 hour delay in the acrophase of activity levels compared to wild-type littermates, and spent less time in REM sleep during the second half of the light period. J20 mice also exhibited decreased NREM delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in A{beta} levels, rotarod performance or the passive avoidance task following chronic mGluR5 inhibitor treatment. ConclusionsJ20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with an mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD. Statement of SignificanceSleep disruption is evolving as an important risk factor as well as phenotype of neurological diseases including Alzheimers disease. This study is novel in determining alterations in the rest-activity rhythm and sleep-wake pattern of J20 Alzheimers disease mice and wild type littermates. Specifically, there is a delay in acrophase with prolonged hyperactivity during the dark cycle, and reduced sleep pressure that was improved by treatment with mGluR5 inhibitor. Critical remaining knowledge gaps and future directions include testing the effects of Alzheimers disease drugs on rescue of sleep and rest-activity patterns in other Alzheimers disease models. These studies are relevant to human Alzheimers disease as monitoring sleep phenotypes may predict disease risk, and therapies that normalize sleep patterns may slow progression.

neuroscience↗

bioRxiv2019

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery causing DNA damage and cell death. BRD4, a BET bromodomain protein and known transcriptional regulator, interacts with P-TEFb to ensure efficient transcriptional elongation by stimulating phosphorylation of RNA Polymerase II (RNAPII). Here we report that disruption of BET bromodomain protein function causes RNAPII pausing on the chromatin and DNA damage affecting cells in S-phase. We find that this persistent, RNAPII-dependent pausing leads to accumulation of RNA:DNA hybrids (R-loops), which are known to lead to transcription-replication conflicts (TRCs), DNA damage, and cell death. Furthermore, we show that resolution of R-loops abrogates BET bromodomain inhibitor-induced DNA damage, and that BET bromodomain inhibition induces both R-loops and DNA damage at sites of BRD4 occupancy. Finally, we see that the BRD4 C-terminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET bromodomain inhibition and that oncogenes which promote transcription and replication exacerbate BET bromodomain inhibitor-induced DNA damage. Together, these findings demonstrate that BET bromodomain inhibitors can damage DNA via induction of R-loops and TRCs in highly replicative cells.

cancer biology↗

bioRxiv2019

A Systems Approach Identifies Enhancer of Zeste Homolog 2 (EZH2) as a Protective Factor in Epilepsy

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after seizure induction robustly increases spontaneous seizure burden weeks later. Thus, EZH2 upregulation is a protective response mounted after a seizure. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.\n\nAuthor SummaryEpilepsy is the fourth most common neurological disorder and has been described since the time of Hippocrates. Despite this, no treatments exist to stop epilepsy progression. This is fundamentally due to the complex nature of the disease. Epilepsy is associated with hundreds if not thousands of gene expression changes in the brain that are likely driven by a few key master regulators called transcription factors and cofactors. Finding the aberrantly acting factors is a complex problem that currently lacks a satisfactory solution. We used a novel datamining tool to define key master regulators of gene expression changes across multiple epilepsy models and patient samples. We find that a nuclear enzyme, EZH2, regulates a large number of genes in the rodent and patient epileptic brain and that its function is protective. Thus, inhibiting EZH2 greatly exacerbates seizure burden. This is the first report of a novel datamining tool to define drivers of large-scale gene changes and is also the first report of EZH2 induction as an endogenous protective response in the epilepsy.

neuroscience↗