The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X-linked chromatin gene (KDM5C): Novel epigenetic mechanism in autism.
Skewed X-inactivation in autistic females flags a novel RNA that may tie body-clock and chromatin paths to autism.
01Research in Context
What this study did
The team looked at blood and brain samples from autistic girls and women.
They checked who had skewed X-inactivation — when one X chromosome shuts down more than the other.
Using RNA sequencing, they hunted for odd gene messages near the KDM5C gene on the X chromosome.
What they found
In females with skewed XCI, a brand-new long RNA message showed up.
This message comes from a jumping gene that copied itself into the KDM5C area.
The extra RNA may switch KDM5C on or off, linking circadian and chromatin paths to autism risk.
How this fits with other research
Jarmolowicz et al. (2008) first saw spotty methylation on the X chromosome in autism brains.
Their work focused on MECP2; Zohreh et al. now widen the map to KDM5C and a new lncRNA.
Ptomey et al. (2021) found methylation changes at the oxytocin receptor in ASD.
Both papers show that tiny epigenetic marks, not full gene breaks, can matter.
Together they build a case for using methylation or RNA panels as quick lab clues.
Why it matters
You can’t fix genes, but you can track their on-off switches.
If a girl presents with autism plus sleep or mood issues, ask about XCI testing.
A simple blood draw may reveal the new KDM5C RNA signal and guide circadian-based supports.
Want CEUs on This Topic?
The ABA Clubhouse has 60+ free CEUs — live every Wednesday. Ethics, supervision & clinical topics.
Join Free →Add a question about irregular sleep to your intake form for autistic females and flag any positive history for possible genetic referral.
02At a glance
03Original abstract
A growing body of evidence supports the potential role of the circadian system and chromatin remodeling genes in autism. Considering the heterogeneity and gender discrepancy in autism, and the complex nature of the epigenetic landscape, identification of biologically relevant epigenetic factors requires reducing heterogeneity using proper subtyping. For this study, we used X chromosome inactivation (XCI) status in females with autism as an epigenetic marker for subtyping and examined the expression level of members of KDM5, a chromatin remodeling gene family. KDM5 are histone demethylases involved in the circadian molecular machinery. We used human blood samples to characterize alternatively spliced KDM5 isoforms and noticed that KDM5C undergoes a complex splicing process. We also identified a KDM5C isoform (KDM5C-3'UTR-lncRNA) containing a novel 3'UTR originated from a retrotransposed gene (retro-SUV39H2) of an autosomal methyltransferase (SUV39H2). This 3'UTR shows 84% sequence homology with long ncRNAs (lncRNAs) and is located 32 kb downstream of KDM5C. The KDM5C-3'UTR-lncRNA isoform was differentially expressed in autistic females with XCI skewness compared with controls. KDM5C plays a crucial role in balancing histone H3K4 methylation states. The identified retro-SUV39H2 originated lncRNA also shows H3K4 marks. By assessing the expression level of alternatively spliced Kdm5 isoforms at different circadian time-points, we showed that some isoforms follow a circadian oscillation pattern in wild type mouse brain.This study provides the first evidence and a suggestive model for the potential role of retrotransposed elements in autism through linking methylases and demethylases, two functionally complementary components of chromatin remodeling, which may collectively contribute to disease etiology through lncRNAs. Autism Res 2019, 12: 1007-1021. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Genes do not function in isolated conditions and their proper expression level also depends on a mechanism called gene regulation. An example of gene regulation is when changes outside DNA sequences influence the function of autism susceptibility genes. Alternative splicing is one type of gene regulation, which produces several versions of a gene (called variants) that may slightly differ from each other and be expressed at different levels in response to environmental changes. The circadian clock is an essential timing mechanism that enables organisms to maintain internal processes in sync with the dynamic environment brought about by the day-night cycle. The goal of this study was to assess if a subset of females with autism with certain genetic marker had a unique pattern of alternative splicing of three circadian genes. We identified a novel variant that is differentially expressed in this subset. Our study provides a novel subject stratification strategy, and a suggestive model of how biologically relevant components of a gene regulatory process may be linked and, possibly, collectively contribute to the etiology of autism.
Autism research : official journal of the International Society for Autism Research, 2019 · doi:10.1002/aur.2116