Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study

Emi Takahashi; Nina Allan; Rafael Peres; Alpen Ortug; Andre J W van der Kouwe; Briana Valli; Elizabeth Ethier; Jacob Levman; Nicole Baumer; Keita Tsujimura; Nauru Idalia Vargas-Maya; Trevor A McCracken; Rosa Lee; Alika K Maunakea

doi:10.3389/fnins.2022.1023665

Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study

Front Neurosci. 2023 Feb 3:16:1023665. doi: 10.3389/fnins.2022.1023665. eCollection 2022.

Authors

Emi Takahashi^{1

2}, Nina Allan³, Rafael Peres³, Alpen Ortug^{1

2}, Andre J W van der Kouwe^{1

2}, Briana Valli⁴, Elizabeth Ethier⁴, Jacob Levman^{1

2

5}, Nicole Baumer⁶, Keita Tsujimura^{1

2}, Nauru Idalia Vargas-Maya³, Trevor A McCracken³, Rosa Lee³, Alika K Maunakea³

Affiliations

¹ Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
² Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
³ Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.
⁴ Department of Behavioral Neuroscience, Northeastern University, Boston, MA, United States.
⁵ Department of Mathematics, Statistics and Computer Science, St. Francis Xavier University, Antigonish, NS, Canada.
⁶ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.

Abstract

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.

Methods: We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.

Results: Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.

Conclusion: These findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

Keywords: DNA methylation; MRI; SVZ; autism; cortex; epigenetic.

Abstract

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