Hominoid SVA-lncRNA AK057321 targets human-specific SVA retrotransposons in SCN8A and CDK5RAP2 to initiate neuronal maturation

Abstract

SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic SVA transposons are enriched for neurodevelopmental disease and transcribed into long non-coding SVA-lncRNAs. Human-specific SVAs in microcephaly CDK5RAP2 and epilepsy SCN8A gene introns repress their expression via transcription factor ZNF91 to delay neuronal maturation. Deleting the SVA in CDK5RAP2 initiates multi-dimensional and in SCN8A selective sodium current neuronal maturation by upregulating these genes. SVA-lncRNA AK057321 forms RNA:DNA heteroduplexes with the genomic SVAs and upregulates these genes to initiate neuronal maturation. SVA-lncRNA AK057321 also promotes species-specific cortex and cerebellum-enriched expression upregulating human genes with intronic SVAs (e.g., HTT, CHAF1B and KCNJ6) but not mouse orthologs. The diversity of neuronal genes with intronic SVAs suggest this hominoid-specific SVA transposon-based gene regulatory mechanism may act at multiple steps to specialize and achieve neoteny of the human brain.

Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex

“…Various biochemical and genetical mechanisms of long-range chromosomal interactions and gene regulation probably have a role including epigenetic processes, chromatin loop formation, nuclear matrix proteins, and RNA, 66,67 and hundreds of genomic anchors that organize chromatin loop domains across the MHC. 68 Since the eight MHC SVA insertions that we described in the present analysis are transcribed, it is likely that the SVA RNAs regulate both the multigene networks and alternative splicing outcomes, involving mechanisms such as SVA exon capture 69,70 and/or interaction with distant promoters and enhancers by way of 3D chromatin structures. 65,67 The mechanisms involved in the long-range regulation of multigene expression by SVA insertions is a challenge that still needs considerable research and modeling with coherent and testable hypotheses.…”

The role of transposable elements in human evolution and methods for their functional analysis: current status and future perspectives

“…Human-specific non-LTR transposon insertions are linked to an increase in transcriptional and splicing variation of the genes they are inserted in, and are enriched in genes expressed more highly in the brain, particularly in undifferentiated neurons (Guichard et al, 2018). In addition, human genes containing intronic SVA are enriched among genes involved in neurodevelopment and neurological diseases (Nadler et al, 2023). As SVAs are repressed by the KRAB-ZNF pathway in human primed embryonic stem cells and epiblast but are de-repressed and function as enhancers in the fetal brain, pineal gland and hippocampus (Trizzino et al, 2018;Pontis et al, 2019), human-specific SVA insertions potentially affect the regulation of genes nearby, especially in the brain.…”

“…AK057321 is upregulated during neuronal maturation, and its depletion results in reduced expression of genes with intronic SVAs such as CHAF1B, KCNJ6, POFUT2, HTT, CDK5RAP2 and SCN8A. Notably, these genes with intronic SVAs are repressed in neural progenitor cells by ZNF91 (Nadler et al, 2023), which binds and recruits H3K9 methyltransferases to SVAs (Jacobs et al, 2014), and are activated with the increase in AK057321 expression during neural maturation (Nadler et al, 2023). Two potential mechanisms have been proposed to elucidate how this lncRNA regulates SVA genes.…”

“…The other possibility is that the lncRNA interacts with ZNF91, thereby preventing ZNF91 from binding to intronic SVAs and subsequently increasing the transcription of genes harboring intronic SVAs. Deficiency of ZNF91 and overexpression of the lncRNA in neural stem cells have been shown to upregulate the expression of genes with intronic SVAs and promote neuronal maturation (Nadler et al, 2023). Depending on the target gene, the control of gene expression through intronic SVA by AK057321 can have varied impacts on the nervous system.…”

“…Depending on the target gene, the control of gene expression through intronic SVA by AK057321 can have varied impacts on the nervous system. AK057321 enhances CDK5RAP2 and SCN8A expression to promote neuronal maturation, while it enhances CHAF1B expression to promote proliferation and stem cell gene expression (Nadler et al, 2023). CDK5RAP2 and SCN8A have a human-specific SVA insertion, while SVA located in the CHAF1B intron is found in humans, chimpanzees and gorillas.…”