title: Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
abstract: Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) plays key roles in neurologic function in health and disease. Neuronal SUMOylation is essential for emotionality and cognition, and this pathway is dramatically activated in post-ischemic neurons, a neuroprotective response to ischemia. It is also known from cell culture studies that SUMOylation modulates gene expression. However, it remains unknown how SUMOylation regulates neuronal gene expression in vivo, in the physiologic state and after ischemia, and modulates post-ischemic recovery of neurologic function. To address these important questions, we used a SUMO1-3 knockdown (SUMO-KD) mouse in which a Thy-1 promoter drives expression of 3 distinct microRNAs against SUMO1-3 to silence SUMO expression specifically in neurons. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia. Microarray analysis was performed in hippocampal CA1 samples, and neurologic function was evaluated. SUMOylation had opposite effects on neuronal gene expression before and after ischemia. In the physiological state, most genes regulated by SUMOylation were up-regulated in SUMO-KD compared to wild-type mice. Brain ischemia/reperfusion significantly modulated the expression levels of more than 400 genes in wild-type mice, with a majority of those genes upregulated. The extent of this post-ischemic transcriptome change was suppressed in SUMO-KD mice. Moreover, SUMO-KD mice exhibited significantly worse functional outcome. This suggests that suppression of global gene expression response in post-ischemic brain due to SUMO knockdown has a negative effect on post-ischemic neurologic function. Together, our data provide a basis for future studies to mechanistically link SUMOylation to neurologic function in health and disease.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, The Fifth Central Hospital of Tianjin, Tianjin, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, The Fifth Central Hospital of Tianjin, Tianjin, China.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Cardiology, The Fifth Central Hospital of Tianjin, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Julia Q
authors.initials: JQ
authors.lastname: Zhao
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: wulf.paschen@duke.edu.
authors.forename: Wulf
authors.initials: W
authors.lastname: Paschen
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: wei.yang@duke.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020127:Recovery of Function / Q000502:physiology*; D012720:Severity of Illness Index; D025841:Small Ubiquitin-Related Modifier Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D025841:Small Ubiquitin-Related Modifier Proteins
keywords: SUMO; brain ischemia; knockdown; microarray; transgenic mice