Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency

Dugger, Sarah A.; Dhindsa, Ryan S.; Sampaio, Gabriela De Almeida; Ressler, Andrew K.; Rafikian, Elizabeth E.; Petri, Sabrina; Letts, Verity A.; Teoh, JiaJie; Ye, Junqiang; Colombo, Sophie; Peng, Yueqing; Yang, Mu; Boland, Michael J.; Frankel, Wayne N.; Goldstein, David B.

doi:10.1371/journal.pgen.1010952

Cited by 3 publications

(1 citation statement)

References 91 publications

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“…Saf-a knockout mouse models show embryonic lethality 36 , whilst conditional deletion in the developing brain leads to rapid cell death of both postmitotic neurons and neural progenitors 37 . Saf-a haploinsufficiency also affects the expression of the neuropeptides arginine vasopressin (Avp) and vasoactive intestinal polypeptide (Vip) resulting in changes in metabolic activity 38 and cell type specific changes in transcription 39,40 . SAF-A is also clinically relevant, as patients with mutations in the gene have neurodevelopmental disorders 17,[41][42][43] .…”

Section: Introductionmentioning

confidence: 99%

Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels

Marenda,

Michieletto,

Czapiewski

et al. 2024

Preprint

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SummaryThe human cell nucleus is comprised of proteins, chromatin and RNA, yet how they interact to form supramolecular structures and drive key biological processes remains unknown. Conflicting models have proposed either a fluid-like or solid-like nature for the intranuclear microenvironment. To reconcile this discrepancy, we investigated the 3D structure and properties of the nuclear interior using experiments and computer simulations. We reveal a novel mechanism where newly synthesized RNA interacts with SAF-A (scaffold attachment factor A, or HNRNPU), forming interconnected microgels degraded by the exonuclease XRN2, leading to dynamic cycles of gelation and fluidization. This emergent microgel network depends on transcription, and is disrupted by SAF-A depletion. It also decreases protein mobility and regulates chromatin compaction by modulating microphase separation, thereby opening transcriptionally active regions. This tunable intranuclear network exhibits scale-dependent fluid- and solid-like features, that we suggest may regulate transcription by controlling access to regulatory proteins and polymerases.HighlightsRNA and SAF-A interact to form clusters that form a nuclear-spanning network of microgelsEmergent microgel network requires transcription and XRN2 activity to undergo gelation and fluidizationMicrogel network impacts nuclear protein mobilityMolecular dynamics modelling shows RNA/SAF-A microgels regulate chromatin decompaction by steric hinderanceGraphical Abstract

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Section: Introductionmentioning

confidence: 99%

Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels

Marenda,

Michieletto,

Czapiewski

et al. 2024

Preprint

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Emerging roles of RNA‐binding proteins in fatty liver disease

Adesanya,

Das,

Kalsotra

2024

WIREs RNA

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A rampant and urgent global health issue of the 21st century is the emergence and progression of fatty liver disease (FLD), including alcoholic fatty liver disease and the more heterogenous metabolism‐associated (or non‐alcoholic) fatty liver disease (MAFLD/NAFLD) phenotypes. These conditions manifest as disease spectra, progressing from benign hepatic steatosis to symptomatic steatohepatitis, cirrhosis, and, ultimately, hepatocellular carcinoma. With numerous intricately regulated molecular pathways implicated in its pathophysiology, recent data have emphasized the critical roles of RNA‐binding proteins (RBPs) in the onset and development of FLD. They regulate gene transcription and post‐transcriptional processes, including pre‐mRNA splicing, capping, and polyadenylation, as well as mature mRNA transport, stability, and translation. RBP dysfunction at every point along the mRNA life cycle has been associated with altered lipid metabolism and cellular stress response, resulting in hepatic inflammation and fibrosis. Here, we discuss the current understanding of the role of RBPs in the post‐transcriptional processes associated with FLD and highlight the possible and emerging therapeutic strategies leveraging RBP function for FLD treatment.This article is categorized under: RNA in Disease and Development > RNA in Disease

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Role of the SAF-A SAP domain in X inactivation, transcription, splicing, and cell proliferation

Sharp,

Sparago,

Thomas

et al. 2024

Preprint

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SAF-A is conserved throughout vertebrates and has emerged as an important factor regulating a multitude of nuclear functions, including lncRNA localization, gene expression, and splicing. SAF-A has several functional domains, including an N-terminal SAP domain that binds directly to DNA. Phosphorylation of SAP domain serines S14 and S26 are important for SAF-A localization and function during mitosis, however whether these serines are involved in interphase functions of SAF-A is not known. In this study we tested for the role of the SAP domain, and SAP domain serines S14 and S26 in X chromosome inactivation, protein dynamics, gene expression, splicing, and cell proliferation. Here we show that the SAP domain serines S14 and S26 are required to maintain XIST RNA localization and polycomb-dependent histone modifications on the inactive X chromosome in female cells. In addition, we present evidence that an Xi localization signal resides in the SAP domain. We found that that the SAP domain is not required to maintain gene expression and plays only a minor role in mRNA splicing. In contrast, the SAF-A SAP domain, in particular serines S14 and S26, are required for normal protein dynamics, and to maintain normal cell proliferation. We propose a model whereby dynamic phosphorylation of SAF-A serines S14 and S26 mediates rapid turnover of SAF-A interactions with DNA during interphase.

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Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency

Cited by 3 publications

References 91 publications

Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels

Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels

Emerging roles of RNA‐binding proteins in fatty liver disease

Role of the SAF-A SAP domain in X inactivation, transcription, splicing, and cell proliferation

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