Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

Nature Reviews Genetics, Год журнала: 2023, Номер 25(1), С. 46 - 60

Опубликована: Июль 25, 2023

Язык: Английский

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AI-MARRVEL — A Knowledge-Driven AI System for Diagnosing Mendelian Disorders

NEJM AI, Год журнала: 2024, Номер 1(5)

Опубликована: Апрель 25, 2024

Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success primary diagnosis.

Язык: Английский

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Structural basis of the Integrator complex assembly and association with transcription factors

Molecular Cell, Год журнала: 2024, Номер 84(13), С. 2542 - 2552.e5

Опубликована: Май 31, 2024

Integrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs. This achieved via two enzymatic activities, RNA endonuclease phosphatase, acting on the promoter-proximally paused polymerase Ⅱ (RNAPⅡ). Yet, it remains unclear how assembly recruitment are regulated what functions many its core subunits are. Here, we report structures human sub-complexes: INTS10/13/14/15 INTS5/8/10/15, an integrative model fully assembled bound to RNAPⅡ elongating (PEC). An in silico protein-protein interaction screen over 1,500 factors (TFs) identified ZNF655 as direct interacting partner INTS13 within Integrator. We propose wherein acts platform TFs that could modulate stability Integrator's association at specific loci regulate attenuation target genes.

Язык: Английский

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De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events

Molecular Cell, Год журнала: 2023, Номер 83(24), С. 4445 - 4460.e7

Опубликована: Ноя. 22, 2023

Язык: Английский

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Mechanistic basis of gene-specific transcription regulation by the Integrator complex

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 25, 2024

ABSTRACT The Integrator complex (INT) regulates gene expression via premature transcription termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. This attenuation is required for cellular response to external stimuli, cell differentiation and neurodevelopment. How gene-specific regulation achieved by INT in an inducible manner remains unclear. Here, we identify two sites on subunits 13/14 that serve as direct binding hubs diverse sets sequence-specific factors (TFs) other effector complexes. TFs co-localize with genome-wide, increase abundance target genes co-regulate transcriptional programs. Consistently, disruption INT-TF contacts impairs sensory cilia formation glucose starvation. Structural analysis places INT’s TF upstream the bubble when attached paused RNAP2, consistent simultaneous TF-promoter association. Our data establish TF-mediated recruitment promoters a widespread mechanism targeted attenuation.

Язык: Английский

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Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are required for their nuclear function

Molecular Cell, Год журнала: 2024, Номер 84(15), С. 2900 - 2917.e10

Опубликована: Июль 19, 2024

Язык: Английский

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Integrator loss leads to dsRNA formation that triggers the integrated stress response

Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Assembly mechanism of Integrator’s RNA cleavage module

Molecular Cell, Год журнала: 2024, Номер 84(15), С. 2882 - 2899.e10

Опубликована: Июль 19, 2024

The modular Integrator complex is a transcription regulator that essential for embryonic development. It attenuates coding gene expression via premature termination and performs 3'-processing of non-coding RNAs. For both activities, requires endonuclease activity harbored by an RNA cleavage module consisting INTS4-9-11. How correct assembly modules achieved remains unknown. Here, we show BRAT1 WDR73 are critical biogenesis factors the human module. They maintain INTS9-11 inactive during maturation physically blocking active site prevent INTS4 association. Furthermore, facilitates import into nucleus, where it joined INTS4. Final release locking mature conformation inositol hexaphosphate (IP

Язык: Английский

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Drosophila as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases

Insects, Год журнала: 2024, Номер 15(11), С. 870 - 870

Опубликована: Ноя. 6, 2024

Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence the limited understanding of origin underlying mechanisms. These disorders often exhibit phenotypic diversity molecular complexity that represent biomedical research. There are more than 6000 different rare affect nearly 300 million people worldwide. However, each disease is low, in consequence, resources dedicated insufficient effectively achieve progress The use animal models investigate mechanisms pathogenesis has become an invaluable tool. Among commonly used research,

Язык: Английский

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