Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing, 2025, Shen & Xiao

[SNT Gatchaman]

Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing
Shen, Jing; Xiao, Chenxu

Identification of cell type–specific and temporally dynamic regulatory features of schizophrenia (SCZ) risk genes is essential for advancing mechanistic neurobiological studies.

This study systematically dissected the genetic architecture and neurodevelopmental mechanisms of SCZ by integrating genome-wide association study (GWAS) data from European (N = 130,644) and East Asian (N = 30,761) population, alongside multi-omics and single-cell sequencing analyses. Cross-method validation identified seven core genes (e.g., MDK, RERE, ERBB4), with RERE exhibiting a notably high eQTL-SCZ colocalization probability of 92.8–93.9%.

Single-cell and epigenetic analyses reveal that the spatiotemporal dynamics of RERE may lead to differences in its mediated SCZ disease risk at the levels of genetic variation and transcriptional regulation. Cleavage Under Targets and Tagmentation (CUT&Tag) confirmed that RERE directly regulates synaptic genes such as PPP4R3B and RPS27L, and its co-expression network was found to be strongly linked to SCZ risk.

This study unveils a RERE-mediated epigenetic-neurodevelopmental axis and suggests that GABAergic neurons may be a potential new target for the treatment of SCZ. Future validation using organoid models and exploration of clinical translation are warranted.

Web | DOI | PDF | Nature Schizophrenia | Open Access

 

[SNT Gatchaman]

(RERE is a currently unpublished ME GWAS hit)

Discussion —

Psychiatric genomics supports the notion that multiple risk variants underlie the genetic architecture of SCZ. However, the neurobiological significance of these genomic findings remains unclear. This study systematically investigated the genetic basis and gene expression characteristics of SCZ by integrating largescale GWAS data from European and East Asian populations. Our study employed a multi-omics approach and identified seven core risk genes (such as MDK and RERE), among which RERE exhibited a notably high eQTL–SCZ colocalization probability.

Single-cell analysis extended the limited evidence on the cellular enrichment of the risk gene RERE, and revealed a specific enrichment pattern in GABAergic neurons.

we confirmed that RERE directly regulates synaptic-related genes, and its co-expression network is closely associated with SCZ risk.

Seven SCZ risk genes identified by multi-omics data analysis are significantly enriched in neurodevelopmental pathways, especially in cell adhesion and synaptic organization processes. This finding provides robust molecular evidence supporting the “neurodevelopmental disorder” hypothesis. From a developmental perspective, these genes exhibited peak activity during the late midprenatal and early childhood periods, coinciding with critical neurodevelopmental windows for SCZ.

Two age peaks of activity (fetal, early childhood) though not two peaks for SCZ disease presentation itself I believe.

RERE encodes a nuclear transcriptional co-repressor involved in embryonic development. Overexpression of RERE may trigger apoptosis, highlighting its critical role in cellular function.

Notably, we found that the core gene RERE exhibited dynamic expression patterns across cell lineages: upregulated in various neuronal populations but downregulated in astrocytes, and elevated in OPCs but unchanged in oligodendrocytes. This spatiotemporal specificity may reflect heterogeneous influences during cell differentiation and development. For instance, OPCs, as precursors to oligodendrocytes, may initiate high RERE expression at the eQTL level, but its expression could decline during gliogenesis.

Through MAGMA-based spatiotemporal dynamic analysis of gene expression and the BrainSpan meta-analysis, we further validated the expression pattern of RERE in glial cells: it exhibited high expression during early development, which gradually decreased as development progressed. In contrast, RERE expression remained relatively stable in neurons.

transcriptomic analysis of L3 and L5 pyramidal neurons in the DLPFC revealed significant differential expression of RERE in L5 but not in L3, with differences also observed between L5 and L3 in the control group. This indicates that RERE transcript levels exhibit complex heterogeneity among neuronal cell types.