Cell type–specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

Chen, Renchao; Liu, Y.; Djekidel, Mohamed Nadhir; Chen, Wenqiang; Bhattacherjee, Aritra; Chen, Zhiyuan; Scolnick, Ed; Zhang, Yi

doi:10.1126/sciadv.abm1077

Cited by 18 publications

(14 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the molecular phenotypes mainly analyzed by transcriptomic profiling, commonly dysregulated pathways include neural transmission and regulation of transcription [54,63,70,88,91,92], in agreement with the findings from human genetics and genomics studies. Also, analyses utilizing results of large-scale human genetics studies have reported enrichment of genetic risk for schizophrenia in genes differentially expressed in the models or molecular targets of the genetically modified genes [88,91].…”

Section: Mouse Modelssupporting

confidence: 82%

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

View full text Add to dashboard Cite

Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.

show abstract

Section: Mouse Modelssupporting

confidence: 82%

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

View full text Add to dashboard Cite

show abstract

“…Some evidence indicates that HTMs might be a potential target in schizophrenia treatment [ 124 , 125 ]. HTMs are divided into lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs).…”

Section: Epigenetic Regulation As Therapeutic Targetsmentioning

confidence: 99%

Epigenetic Targets in Schizophrenia Development and Therapy

2023

View full text Add to dashboard Cite

Schizophrenia is regarded as a neurodevelopmental disorder with its course progressing throughout life. However, the aetiology and development of schizophrenia are still under investigation. Several data suggest that the dysfunction of epigenetic mechanisms is known to be involved in the pathomechanism of this mental disorder. The present article revised the epigenetic background of schizophrenia based on the data available in online databases (PubMed, Scopus). This paper focused on the role of epigenetic regulation, such as DNA methylation, histone modifications, and interference of non-coding RNAs, in schizophrenia development. The article also reviewed the available data related to epigenetic regulation that may modify the severity of the disease as a possible target for schizophrenia pharmacotherapy. Moreover, the effects of antipsychotics on epigenetic malfunction in schizophrenia are discussed based on preclinical and clinical results. The obtainable data suggest alterations of epigenetic regulation in schizophrenia. Moreover, they also showed the important role of epigenetic modifications in antipsychotic action. There is a need for more data to establish the role of epigenetic mechanisms in schizophrenia therapy. It would be of special interest to find and develop new targets for schizophrenia therapy because patients with schizophrenia could show little or no response to current pharmacotherapy and have treatment-resistant schizophrenia.

show abstract

“…The cellular phenotype resembles that of ASD ( Hutsler and Zhang, 2010 ; Varghese et al, 2017 ; Weir et al, 2018 ), another common disorder that is often caused by altered H3K4 methylation ( Shen et al, 2014 ; Collins et al, 2019 ). Despite conflicting findings, altered H3K4 methylation has consistently been shown to induce aberrant pruning activity and dendritic structure ( Sellgren et al, 2019 ; Chen et al, 2022 ; Wang et al, 2022 ). Further exploration of the roles of H3K4 modifications in microglial function, dendritic pruning, brain network activity, and memory formation and retrieval will increase our understanding of not only KMT2F-associated schizophrenia, but also other forms of schizophrenia and ASD.…”

Section: Extending the Rdeo Findings To Common Complex Diseasesmentioning

confidence: 99%

Rare diseases of epigenetic origin: Challenges and opportunities

Merrill

Sharma

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene–disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

show abstract

Cell type–specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

Cited by 18 publications

References 73 publications

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Epigenetic Targets in Schizophrenia Development and Therapy

Rare diseases of epigenetic origin: Challenges and opportunities

Contact Info

Product

Resources

About