Sf3b4 regulates chromatin remodeler splicing and Hox expression

Kumar, Shruti; Alam, Sabrina; Bareke, Eric; Beauchamp, Marie‐Claude; Dong, Yanchen; Chan, Wesley; Majewski, Jacek; Jerome-Majewska, Loydie A.

doi:10.1016/j.diff.2023.04.004

Cited by 6 publications

(17 citation statements)

References 60 publications

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“…Overall, we show that craniofacial malformations similar to those found in patients with SF3B4-related syndromes were present in the majority of Sf3b4 NCC mutants. In addition to craniofacial defects, Sf3b4 ncc/embryos also had vertebral abnormalities like those seen in Sf3b4 +/embryos 21,22 . Therefore, the Sf3b4 NCC mutant embryos described herein are the first to model the spectrum of malformations and expressivity found from Nager to Rodriguez syndrome 1,3 .…”

Section: Discussionmentioning

confidence: 83%

“…Our aim is to uncover the etiology of malformations seen in SF3B4-related syndromes. Previous work by our group and the group of Yamada et al 21,22 , showed that mice with heterozygous mutation of Sf3b4 did not model craniofacial malformations seen in patients, but had growth retardation, microcephaly, as well as homeotic posteriorization of the axial skeleton. Furthermore, although craniofacial and eye abnormalities found in SF3B4-related patients have been phenocopied in zebrafish and Xenopus embryos with knock down of Sf3b4 23,24 , vertebrae and heart defects were not found.…”

Section: Introductionmentioning

confidence: 77%

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Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Kumar,

Bareke,

Lee

et al. 2024

Preprint

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Pathogenic variants in SF3B4 are responsible for the acrofacial disorders Nager and Rodriguez Syndrome, also known as SF3B4-related Syndromes, associated with malformations in the head, face, limbs, vertebrae as well as the heart. To uncover the etiology of craniofacial malformations found in SF3B4-related syndromes, mutant mouse lines with homozygous deletion of Sf3b4 in neural crest cells (NCC) were generated. Like in human patients, these embryos had craniofacial and cardiac malformations with variable expressivity and penetrance. The severity and survival of Sf3b4 NCC mutants was modified by the level of Sf3b4 in neighbouring non NCC. RNA sequencing analysis of heads of embryos prior to morphological abnormalities showed significant changes in expression of genes forming the NCC regulatory network, as well as an increase in exon skipping. We identified several key transcription factors and histone modifiers involved in craniofacial and cardiac development with increased exon skipping. Increased exon skipping was also associated with use of a more proximal branch point, as well as an enrichment in thymidine bases in the 50bp around the branch points. We propose that decrease in Sf3b4 causes changes in the expression and splicing of transcripts required for proper craniofacial and cardiac development, leading to abnormalities.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 77%

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Kumar,

Bareke,

Lee

et al. 2024

Preprint

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“…RNA splicing abnormalities: SF3B1, SF3B2 and SF3A1 are involved in the assembly of the nuclear spliceosome complex. Abnormalities in RNA splicing have been associated with certain inherited skin diseases and skin tumours 85,86 …”

Section: Resultsmentioning

confidence: 99%

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets

Liu,

Lu,

Qiu

et al. 2023

International Wound Journal

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Pathological scarring resulting from traumas and wounds, such as hypertrophic scars and keloids, pose significant aesthetic, functional and psychological challenges. This study provides a comprehensive transcriptomic analysis of these conditions, aiming to illuminate underlying molecular mechanisms and potential therapeutic targets. We employed a co‐expression and module analysis tool to identify significant gene clusters associated with distinct pathophysiological processes and mechanisms, notably lipid metabolism, sebum production, cellular energy metabolism and skin barrier function. This examination yielded critical insights into several skin conditions including folliculitis, skin fibrosis, fibrosarcoma and congenital ichthyosis. Particular attention was paid to Module Cluster (MCluster) 3, encompassing genes like BLK, TRPV1 and GABRD, all displaying high expression and potential implications in immune modulation. Preliminary immunohistochemistry validation supported these findings, showing elevated expression of these genes in non‐fibrotic samples rich in immune activity. The complex interplay of different cell types in scar formation, such as fibroblasts, myofibroblasts, keratinocytes and mast cells, was also explored, revealing promising therapeutic strategies. This study underscores the promise of targeted gene therapy for pathological scars, paving the way for more personalised therapeutic approaches. The results necessitate further research to fully ascertain the roles of these identified genes and pathways in skin disease pathogenesis and potential therapeutics. Nonetheless, our work forms a strong foundation for a new era of personalised medicine for patients suffering from pathological scarring.

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“…Mouse embryos with heterozygous Sf3b4 mutation show axial skeleton and forebrain defects, while Sf3b4 homozygous deletion is embryonic lethal (Yamada et al, 2020). RNA-seq analyses of Sf3b4 heterozygous mutants reveal a disruption in Hox gene expression and aberrant splicing of several chromatin remodelers known to regulate Hox genes (Kumar et al, 2023). In X. laevis, morpholino-mediated knockdown of sf3b4 results in a reduction of NC gene expression at neurula and tailbud stages, causing a reduction of NC-derived craniofacial cartilages at tadpole stages through a mechanism that involves apoptosis (Devotta et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Previous work in mouse models has shown that a loss of SF3B4 affects the axial skeleton and the forebrain (Yamada et al, 2020;Kumar et al, 2023), with a disruption in Hox gene expression and aberrant splicing of several chromatin remodelers (Kumar et al, 2023). In Xenopus laevis, morpholino-mediated knockdown of sf3b4 results in a loss of NC gene expression and causes a reduction or loss of craniofacial cartilages at tadpole stages through a mechanism that involves increased apoptosis (Devotta et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sf3b4mutation inXenopus tropicaliscauses RNA splicing defects followed by massive gene dysregulation that disrupt cranial neural crest development

Griffin,

Coppenrath,

Khan

et al. 2024

Preprint

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Nager syndrome is a rare craniofacial and limb disorder characterized by midface retrusion, micrognathia, absent thumbs, and radial hypoplasia. This disorder results from haploinsufficiency of SF3B4 (splicing factor 3b, subunit 4) a component of the pre-mRNA spliceosomal machinery. The spliceosome is a complex of RNA and proteins that function together to remove introns and join exons from transcribed pre-mRNA. While the spliceosome is present and functions in all cells of the body, most spliceosomopathies - including Nager syndrome - are cell/tissue-specific in their pathology. In Nager syndrome patients, it is the neural crest (NC)-derived craniofacial skeletal structures that are primarily affected. To understand the pathomechanism underlying this condition, we generated a Xenopus tropicalis sf3b4 mutant line using the CRISPR/Cas9 gene editing technology. Here we describe the sf3b4 mutant phenotype at neurula, tail bud, and tadpole stages, and performed temporal RNA-sequencing analysis to characterize the splicing events and transcriptional changes underlying this phenotype. Our data show that while loss of one copy of sf3b4 is largely inconsequential in Xenopus tropicalis, homozygous deletion of sf3b4 causes major splicing defects and massive gene dysregulation, which disrupt cranial NC cell migration and survival, thereby pointing at an essential role of Sf3b4 in craniofacial development.

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Sf3b4 regulates chromatin remodeler splicing and Hox expression

Cited by 6 publications

References 60 publications

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets

Sf3b4mutation inXenopus tropicaliscauses RNA splicing defects followed by massive gene dysregulation that disrupt cranial neural crest development

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