Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

Abstract

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.

Histone Methyltransferase SETDB1 Regulates the Development of Cortical Htr3a-Positive Interneurons and Mood Behaviors

“…2A), which belongs to the LTR/ERV1 family. SETDB1/KAP1 complex is critical for ERV silencing, and de-repression of ERVs due to the loss of SETDB1 has been reported in many cell types, including neurons (17,18). Once activated, some ERVs behave as enhancers to affect nearby genes (12,15,18,25).…”

“…SETDB1 (SET domain, bifurcated 1) is one of the histone methyltransferases mediating H3K9 trimethylation (12). It primarily functions as a transcriptional repressor (13)(14)(15), which acts not only directly on the gene promoters but also through long-range chromatin interactions (16,17). SETDB1 is an essential gene during embryonic development and is J o u r n a l P r e -p r o o f highly expressed in the fetal brain (16,18).…”

ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes

“…It is also possible that there is a de-regulation of TEs that are more distal to Mafb gene that are important for the regulation of Mafb in islets. Indeed, several studies have shown that TEs can serve as enhancers, are associated with open chromatin regions, contain transcription factor binding sites, and are involved in cell-type specific chromatin domain organization and gene regulation [ 71 – 73 ]. Alternately, the dysregulation of other genes in endocrine cells that are important for Mafb expression could be affected.…”

3D Genome Plasticity in Normal and Diseased Neurodevelopment

“…Similar mechanisms may shape neuronal and glial 3D genomes in the rodent lineage. In support of this, a recent study [ 38 ] reported that cell-type specific adaptations of chromosomal megadomains shape the 3D genome in mouse lines, particularly those with high genomic densities of phylogenetically young murine Endogenous Retrovirus (ERV) retroelements. They observed that locus-specific densities of ERV elements, which underwent a dramatic expansion in Mus musculus -derived inbred lines as compared to the wild-derived Mus Spretus inbred strain that diverged from Mus musculus 1.5 million years ago [ 39 ], are associated with much higher inter- and intra-chromosomal contact frequencies in neuronal chromatin [ 38 ].…”

“…This effect was absent in the surrounding non-neuronal (incl. glial) cells, pointing to important genome-scale differences in the chromosomal contact map of mature neurons even between closely related mouse species, and could be a reflection of neurotoxic and neuroinflammatory potential of ERV retroelements when unsilenced [ 38 ].…”