Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Santos-Terra, Júlio; Deckmann, Iohanna; Fontes-Dutra, Mellanie; Schwingel, Gustavo Brum; Bambini-Júnior, Victorio; Gottfried, Carmem

doi:10.1002/jdn.10141

Cited by 16 publications

(12 citation statements)

References 267 publications

(273 reference statements)

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“…Transcription and translation constitute key layers of dysfunction in NDDs (Ayhan and Konopka, 2019; Crino, 2016; Magdalon et al, 2017; Santos-Terra et al, 2021). Mutations in many TFs affect neurodevelopment by altering the activity of master regulators such as the RE-1 silencing transcription factor (REST), as shown for the high-confidence ASD/ID genes CHD8 and MECP2 (Ballas et al, 2005; Katayama et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Mihailovich

Germain

Shyti

et al. 2022

Preprint

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Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Mihailovich

Germain

Shyti

et al. 2022

Preprint

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“…This study aims to unravel the role of MD GVs in genetic regulation by focusing on regulatory variation following two complementary approaches: cis-eQTLs and TF binding alterations. Both are key to identifying potentially causal genes and understanding gene expression regulation [6, 8]; as reported by supporting evidence for its association with other mental disorders [40][41][42] and with MD in particular [43][44][45]. The regulatory variation analysis pipelines we have designed and implemented involve ne-mapping, cis-eQTL colocalization, transcription factor binding analysis and chromatin accessibility data; specially designed to perform well when full-genome summary statistics are not available [46].…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Preprint

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Background: Major Depression is the leading cause of impairment worldwide. The understanding of its molecular underpinnings is key to identifying new potential biomarkers and drug targets to alleviate its burden in society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of Major Depression associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with Major Depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis using GTEx data and alteration of transcription factor binding sites with pattern matching approaches and chromatin accessibility data.Results: The fine-mapping of major depression genetic variants uncovered putative causally associated variants whose proximal genes were linked with Major Depression pathophysiology. Four genetic variants altering the expression of 5 genes were found by colocalization analysis, highlighting the role of SLC12A5, involved in chlorine homeostasis in neurons, and MYRF, related with central nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of the genomic variant rs62259947 in modulating the expression of P4HTM through the alteration of YY1 binding site, altogether regulating hypoxia response.Conclusions: The combination of GWAS signals, cis-eQTL, transcription factor binding site information and active regulatory regions in the chromatin, enabled the prioritization of putative causal genetic variants in Major Depression. Importantly, our pipeline can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

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“…This study aims to unravel the role of MD GVs in genetic regulation by focusing on regulatory variation following two complementary approaches: cis-eQTLs and TF binding alterations. Both are key to identifying potentially causal genes and understanding gene expression regulation [ 6 , 8 ], as reported by supporting evidence for its association with other mental disorders [ 53 , 54 , 55 ] and with MD in particular [ 56 , 57 , 58 ]. The regulatory variation analysis pipelines we have implemented involve fine-mapping, cis-eQTL colocalization, transcription factor binding analysis, and chromatin accessibility data, specially designed to perform well when full-genome summary statistics are not available [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Genes

View full text Add to dashboard Cite

Understanding the molecular basis of major depression is critical for identifying new potential biomarkers and drug targets to alleviate its burden on society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of major depression-associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with major depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis and alteration of transcription factor binding sites. The fine-mapping process uncovered putative causally associated variants whose proximal genes were linked with major depression pathophysiology. Four colocalizing genetic variants altered the expression of five genes, highlighting the role of SLC12A5 in neuronal chlorine homeostasis and MYRF in nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of rs62259947 in modulating P4HTM expression by altering the YY1 binding site, altogether regulating hypoxia response. Overall, our pipeline could prioritize putative causal genetic variants in major depression. More importantly, it can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

show abstract

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Cited by 16 publications

References 267 publications

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

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