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bioRxiv · 10.1101/077214

Traumatic brain injury causes retention of long introns in metabolic genes via regulation of intronic Histone 3 lysine 36 methylation levels in the sub-acute phase of injury

Arko Sen·Wen Wu·Oluwademi Okikiolu Nuga·Jenny Liu·Rayanne Burl·Katherine Gurdziel·Roger Pique-Regi·Maik Hüttemann·Douglas M Ruden
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Abstract

Traumatic brain injury (TBI) can cause persistent pathological alteration of neurons. This may lead to cognitive dysfunctions, depression, and even increased susceptibility to life threatening diseases, such as epilepsy and Alzheimers Disease. To investigate the underlying genetic and molecular basis of TBI, Wasserman and colleagues developed an inexpensive and reproducible model for simulating TBI in Drosophila melanogaster (Fruit Fly). Using a modified version of this high impact trauma (HIT) device, we subjected w1118 fruit flies to mild closed head trauma. To determine the transcriptomic changes that contribute to survival post TBI, we collected fly heads from the survivors at 2 time points; 4 hours and 24 hours post-trauma. Mild TBI had limited impact on the steady state RNA levels but showed large perturbations in alternative splicing (AS) 24 hours post-trauma. Classification of these AS changes showed selective retention (RI) of long introns (>81bps), with a mean size of ~3000bps. Some of these RI genes also showed a significant reduction in transcript abundance and were specifically enriched in genes involved in mitochondrial metabolism. The RI are enriched in ACACACA motifs known to bind to Smooth (SM), an hnRNPL class of splicing factor. Mutating SM (sm4/Df) resulted in reversal of RI observed 24 hours post-trauma, and in some cases, elimination of basal levels of RI in long introns. This observation suggests that SM is critical regulator of RI and that this process is enhanced by TBI. Interestingly, chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) for histone 3 lysine 36 trimethylation (H3K36me3) revealed increased levels of this histone modification in retained introns post-trauma. Consistent with this observation, mutations in lysine specific demethylase 4A (KDM4A), which de-methylate H3K36me3, increased RI in many of the same long introns affected by TBI. Additionally, higher H3K36me3 levels are observed around intronic SM-binding motifs post-trauma, suggesting interaction between H3K36me3 and SM binding to intronic splicing suppressor sites might be responsible for increasing RI of metabolic genes as a novel mechanism to improve survival after TBI.

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Arko Sen, Wen Wu, Oluwademi Okikiolu Nuga, Jenny Liu, Rayanne Burl, Katherine Gurdziel, Roger Pique-Regi, Maik Hüttemann, Douglas M Ruden. 2016-09-25. Traumatic brain injury causes retention of long introns in metabolic genes via regulation of intronic Histone 3 lysine 36 methylation levels in the sub-acute phase of injury. https://doi.org/10.1101/077214

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