5-hydroxymethylcytosine in autism spectrum disorder: an investigation of 5-hydroxymethylcytosine profiles in Mecp2 and Fmr1 knockout and overexpression mouse models 公开
Manupipatpong, Sasicha (2017)
Published
Abstract
Autism spectrum disorders (ASDs) comprise a group of disorders characterized by impaired language, social, and communication skills, in addition to restrictive behaviors or stereotypies. Symptoms begin to manifest in early development and persist throughout the affected individual's life. With a prevalence of 1.5% in developed countries and relatively high comorbidity rates, but still no clear underlying mechanism that unifies the heterogeneous phenotypes, it is a field of research that warrants further exploration. 5-hydroxymethylcytosine (5-hmC) is an epigenetic modification whose importance in neurodevelopmental and neurodegenerative disorders has been demonstrated. By investigating the 5-hmC profiles of mouse models for Rett Syndrome and Fragile X Syndrome, two autism spectrum disorder-linked monogenic disorders, in addition to overexpression models for their associated genes (MECP2 and FMR1, respectively), we were able to identify possible pathways in which 5-hydroxymethylation could play a role. Additionally, we characterized the nature of 5-hydroxymethylation in these mouse models and proposed hypoxia-inducible factor 1-alpha (HIF1A) and glucocorticoid modulatory element-binding protein 1 (GMEB1) as a possible players based on transcription factor motif analysis of the data.
Table of Contents
Introduction ................................................................................................ 1
Table 1. DSM-V Diagnostic Criteria for ASD ....................................................... 1
Figure 1. Cytosine Modification Pathways .......................................................... 4
Figure 2. FMR1 gene CGG repeat expansions in Fragile X Syndrome ..................... 5
Figure 3. MECP2 protein schematic detailing main functional domains and
interactions .................................................................................................. 6
Figure 4. T4 bacteriophage β-glucosyltransferase-facilitated 5-hmC capture .......... 8
Results ....................................................................................................... 8
Figure 5. Expected gene annotation for mouse genome ...................................... 9
Figure 6. Gene annotation for differentially 5-hydroxymethylated regions in each
mouse model ................................................................................................ 9
Figure 7. Gene annotation for differentially 5-hydroxymethlated regions by
percent difference of 5-hmC in knockout and overexpression groups ................... 13
Figure 8. 5-hmC capture enrichment plots for various genomic regions ................ 16
Figure 9. DAVID gene ontology for HOMER-identified 5-hmC peaks for each
mouse model ............................................................................................... 17
Figure 10. DAVID gene ontology for differentially 5-hydroxymethlated regions
by percent difference of 5-hmC in knockout and overexpression groups ............... 19
Figure 11. CentriMo centrally enriched transcription factor motifs in differentially
5-hydroxymethylated regions ......................................................................... 11
Figure 12. HIF1A ChIP real-time PCR results ..................................................... 22
Figure 13. Venn diagram of autism spectrum disorder candidate genes (SFARI)
within differentially 5-hydroxymethylated regions .............................................. 25
Discussion .................................................................................................. 25
Methods ...................................................................................................... 29
References .................................................................................................. 32
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