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TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

ABSTRACT: THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants do not alter the expression of TREX dimer component proteins in human cells, but reduced binding affinity to ALYREF implicates impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions, developmental biology implicated in TIDS neuropathology.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE245121 | GEO | 2023/10/17

REPOSITORIES: GEO

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TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

Project description:TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

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A member of transcription/export complex (TREX), THOC5 controls elongation rate by recruiting CDK12.

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The nuclear pore-associated TREX-2 complex employs the Mediator Med31 submodule as a docking site to regulate gene expression

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Compromised THOC2, a TREX mRNA export complex scaffold protein, leads to R-loop accumulation, DNA damage and adverse neurodevelopmental outcomes in mice and men

Project description:TREX (Transcription-Export) is a highly conserved multi-subunit protein complex that, besides its established role in mRNA export from nucleus to cytoplasm, is involved in transcriptional regulation, stem cell maintenance, 3’ mRNA processing, mitotic progression, and genome stability in eukaryotic cells. TREX is composed of a six subunit THO core complex (THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7) and eight accessory proteins. We have implicated the X-chromosome THOC2 gene, which encodes the scaffold protein of the THO complex, in a clinically variable neurodevelopmental disorder (NDD) with intellectual disability (ID) as the core phenotype. To study the function of this essential eukaryotic gene and the mechanisms underlying its NDD outcomes, we generated a clinically-relevant mouse model based on a hypomorphic Thoc2 exon37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mice brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Differentiated cortical neurons of Thoc2Δ/Y mice show perturbed synaptic and electrophysiological properties underlined by increased DNA damage comparable to the primary cells of patients with THOC2 pathogenic variants. Altogether, our data suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and men, and DNA damage-associated functional alterations are at the root of THOC2 syndrome. Overall, we suggest that THOC2 is a major, conserved player in the efficient resolution of R-loops, a process essential for normal brain development and function.

2023-12-15 | GSE245539 | GEO

The nuclear pore-associated TREX-2 complex employs the Mediator Med31 submodule as a docking site to regulate gene expression

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Expression profile of HeLa THOC1-depleted stable cell lines (HeTH-4)

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