TY - JOUR
T1 - Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions
AU - Chandrasekaran, Sandhya
AU - Espeso-Gil, Sergio
AU - Loh, Yong Hwee Eddie
AU - Javidfar, Behnam
AU - Kassim, Bibi
AU - Zhu, Yueyan
AU - Zhang, Yuan
AU - Dong, Yuhao
AU - Bicks, Lucy K.
AU - Li, Haixin
AU - Rajarajan, Prashanth
AU - Peter, Cyril J.
AU - Sun, Daijing
AU - Agullo-Pascual, Esperanza
AU - Iskhakova, Marina
AU - Estill, Molly
AU - Lesch, Bluma J.
AU - Shen, Li
AU - Jiang, Yan
AU - Akbarian, Schahram
N1 - Funding Information:
The authors thank all members of the Akbarian lab for constructive comments and discussions; E.X., C.R. and A.C. for generous access to sequencing equipment; L.W. and staff at the New York Genome Center for logistical support; M.S. and D.S. for guidance on the PacBio SMRT-Seq protocol; and L.M. for his insights into human retrovirology. Nuclei sorting was performed at the Flow Cytometry CoRE at the Icahn School of Medicine at Mount Sinai. Microscopy preparation and imaging was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai. RNA-Seq library preparation and next-generation sequencing was performed at the Genomics CoRE at the Icahn School of Medicine at Mount Sinai. We thank Dr. B.R. Cullen (Duke University) for the anti-IAP antibody gift. This work was supported by grants R01MH106056 (S.A.), R01MH117790 (S.A.), and P50MH096890 (S.A.), National Natural Science Foundation of China 81971272 (Y.J.), and T32-AG049688 (S.C.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites. We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.
AB - Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites. We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.
UR - http://www.scopus.com/inward/record.url?scp=85121327241&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26862-z
DO - 10.1038/s41467-021-26862-z
M3 - Article
C2 - 34903713
AN - SCOPUS:85121327241
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7243
ER -