Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress
Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown....
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| Format: | Article |
| Language: | English |
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Elsevier
2016-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115300899 |
| _version_ | 1818352376209211392 |
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| author | Sisi Li Ligia A. Papale Qi Zhang Andy Madrid Li Chen Pankaj Chopra Sündüz Keleş Peng Jin Reid S. Alisch |
| author_facet | Sisi Li Ligia A. Papale Qi Zhang Andy Madrid Li Chen Pankaj Chopra Sündüz Keleş Peng Jin Reid S. Alisch |
| author_sort | Sisi Li |
| collection | DOAJ |
| description | Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. |
| first_indexed | 2024-12-13T18:52:39Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:52:39Z |
| publishDate | 2016-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-053c4e995baa4e308f08d0bdafc489952022-12-21T23:34:54ZengElsevierNeurobiology of Disease1095-953X2016-02-018699108Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stressSisi Li0Ligia A. Papale1Qi Zhang2Andy Madrid3Li Chen4Pankaj Chopra5Sündüz Keleş6Peng Jin7Reid S. Alisch8Department of Psychiatry University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USADepartment of Psychiatry University of Wisconsin, Madison, WI, USADepartment Statistics, Biostatistics, and Medical Informatics, University of Wisconsin, Madison, WI, USADepartment of Psychiatry University of Wisconsin, Madison, WI, USA; Endocrinology and Reproductive Physiology Training Program, University of Wisconsin, Madison, WI, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA, USADepartment Statistics, Biostatistics, and Medical Informatics, University of Wisconsin, Madison, WI, USADepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA, USADepartment of Psychiatry University of Wisconsin, Madison, WI, USA; Correspondence author at: Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, 6001 Research Park Blvd., Madison, WI 53719-1176, USA.Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders.http://www.sciencedirect.com/science/article/pii/S0969996115300899Acute stressEpigeneticsDNA methylation5-HydroxymethylcytosineGene expression |
| spellingShingle | Sisi Li Ligia A. Papale Qi Zhang Andy Madrid Li Chen Pankaj Chopra Sündüz Keleş Peng Jin Reid S. Alisch Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress Neurobiology of Disease Acute stress Epigenetics DNA methylation 5-Hydroxymethylcytosine Gene expression |
| title | Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress |
| title_full | Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress |
| title_fullStr | Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress |
| title_full_unstemmed | Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress |
| title_short | Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress |
| title_sort | genome wide alterations in hippocampal 5 hydroxymethylcytosine links plasticity genes to acute stress |
| topic | Acute stress Epigenetics DNA methylation 5-Hydroxymethylcytosine Gene expression |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115300899 |
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