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Distinct SOX9 single-molecule dynamics characterize adult differentiation and fetal-like reprogrammed states in intestinal organoids

ABSTRACT: Transcription factors (TFs) mediate gene expression changes during differentiation and development. However, how TF biophysical properties and abundance dynamically regulate specific cell state transitions remains poorly understood. Using automated live-cell single-molecule tracking (SMT) in intestinal organoid models, we revealed an expression level-independent decrease in the fraction of immobile SOX9 molecules during differentiation from ~48% to ~38%, largely dependent on DNA binding. Strikingly, long-term SOX9 overexpression caused organoids to transition from budding to spheroid morphology accompanied by increased proliferation and a loss in gene expression signatures for intestinal identity and function. In this fetal-like reprogrammed state, a larger fraction of partially self-interacting SOX9 molecules (~61%) binds to DNA. Our results suggest context-dependent SOX9 single-molecule dynamics during adult intestinal differentiation and fetal-like reversion in consequence to long-term SOX9 overexpression. Our work underpins the power of our automated live-cell SMT framework to generate testable hypotheses towards unraveling molecular mechanisms underlying tissue-level phenotypes. Contact: nikewalther.science@gmail.com

ORGANISM(S): Mus musculus

PROVIDER: GSE287653 | GEO | 2026/01/21

REPOSITORIES: GEO

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Distinct SOX9 single-molecule dynamics characterize adult differentiation and fetal-like reprogrammed states in intestinal organoids

Project description:Distinct SOX9 single-molecule dynamics characterize adult differentiation and fetal-like reprogrammed states in intestinal organoids

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Project description:The histone variant H2A.Z marking permissive chromatin is preferentially deposited at promoter-proximal +1 nucleosomes by the multicomponent SWR1 chromatin remodeler. Although SWR1 targeting to nucleosome-depleted regions (NDRs) is directed by its free DNA length sensing module, how the remodeler is guided preferentially to flanking +1 nucleosomes has been enigmatic. Here, we show by live-cell, single-molecule tracking (SMT) that SWR1 subunits Bdf1 and Yaf9 harboring bromo and YEATS acetyl-histone reader domains are required for quantitative chromatin binding via distinct kinetic mechanisms: Bdf1 increases SWR1 association, Yaf9-YEATS reduces disassociation. Notably, SMT and genome-wide ChIP-exo reveals Bdf1 and Yaf9 contributions to SWR1 targeting globally and histone exchange at +1 nucleosomes. Our findings highlight the native biochemistry of histone readers and suggest a broadly applicable, two-stage mechanism wherein acetyl-histone interactions initially constrain 3D diffusion of SWR1 to increase local concentration, followed by stochastic 1D diffusion at NDRs with directional capture by acetylated +1 nucleosomes.

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Sox9 determines translational capacity during early chondrogenic differentiation of ATDC5 cells by regulating expression of ribosome biogenesis factors and ribosomal proteins

Project description:Introduction: In addition to the well-known cartilage extracellular matrix-related expression of Sox9, we demonstrated that chondrogenic differentiation of progenitor cells is driven by a sharply defined bi-phasic expression of Sox9: an immediate early and a late (extracellular matrix associated) phase expression. In this study we aimed to determine what biological processes are driven by Sox9 during this early phase of chondrogenic differentiation. Materials: Sox9 expression in ATDC5 cells was knocked-down by siRNA transfection at the day before chondrogenic differentiation or at day 6 of differentiation. Samples were harvested at 2 hours, and 7 days of differentiation. The transcriptomes (RNA-seq approach) and proteomes (Label-free proteomics approach) were compared using pathway and network analyses. Total protein translational capacity was evaluated with the SuNSET assay, active ribosomes with polysome profiling and ribosome modus with bicistronic reporter assays. Results: Early Sox9 knockdown severely inhibited chondrogenic differentiation weeks later. Sox9 expression during the immediate early phase of ATDC5 chondrogenic differentiation regulated the expression of ribosome biogenesis factors and ribosomal protein subunits. This was accompanied by decreased translational capacity following Sox9 knockdown, and this correlated to lower amounts of active mono- and polysomes. Moreover, cap- versus IRES-mediated translation was altered by Sox9 knockdown. Sox9 overexpression was able to induce reciprocal effects to the Sox9 knockdown. Conclusion: Here we identified an essential new function for Sox9 during early chondrogenic differentiation. A role for Sox9 in regulation of ribosome amount, activity and/or composition may be crucial in preparation for the demanding proliferative phase and subsequent cartilage extracellular matrix-production of chondroprogenitors in the growth plate in vivo.

2021-06-18 | PXD024715 | Pride

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2019-05-15 | E-MTAB-7660 | biostudies-arrayexpress

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2012-03-23 | E-GEOD-35481 | biostudies-arrayexpress

In fetal testis, SOX9 acts on transcription and splicing of its targets genes through binding to genomic regions with conserved signatures [RNA-seq]

Project description:In mammals, male fate is under the control of the master transcriptional regulator, SOX9: in its presence, somatic precursor cells of the embryonic gonads differentiate into Sertoli cells, the main organizers of testicular differentiation. Therefore, analyzing target genes of this transcription factor allows understanding mechanisms of cellular commitment at the genomic level. With the use of ChIP-seq in murine and bovine wild-type testes combined with RNAseq from mouse testes lacking SOX9, we identified SOX9 target genes in the mammalian fetal gonad. SOX9 in murine and bovine fetal testes binds to a large set of genes conserved among mammals, including those with well-established roles in testis and ovary development. RNAseq analysis shows that testis and ovary display sex specific RNA splicing and that SOX9 mediates both target gene transcription and differential splicing. Regions bound by SOX9 are predominantly 5’ proximal or intra-genic, and display a specific genomic features that we call "Sertoli cell signatures" or SCS. The SCS is conserved among mammals and comprises multiple binding motifs for the Sertoli reprogramming factors SOX9, GATA4 and DMRT1; indeed, independent DMRT1 ChIP-seq confirms the enrichment of the SCS. Bioinformatic analysis of SCSs regions predicts novel regulatory mechanisms prompting functional validation. For example, we detected SCS in target genes of the nuclear factor TRIM28 and we show experimentally that SOX9 and TRIM28 proteins interact in fetal testis.

2016-12-15 | GSE81489 | GEO

In fetal testis, SOX9 acts on transcription and splicing of its targets genes through binding to genomic regions with conserved signatures [ChIP-seq]

2016-12-15 | GSE81488 | GEO

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Project description:In this study, we performed single-cell transcriptional profiling of human embryonic and fetal gut samples obtained from 9 human embryos spanning ages 6-10 PCW and three regions (duo-jejunum, ileum and colon). Additionally, we profile mucosal biopsies from the terminal ileum of healthy children aged 4-12 years (n = 8) as well as a group of children newly diagnosed with Crohn’s disease (CD) (n = 7), a common form of IBD. Tissue samples were treated using an enzymatic dissociation protocol and single cell suspensions were then processed using the 3’v2 10x Genomics Chromium workflow. In a subset of samples, the intestinal epithelial cell fraction was enriched by performing magnetic bead sorting for EPCAM. In total, we generate single cell transcriptomes of ~90,000 primary human intestinal cells providing a rich resource and detailed roadmap. Using this data as well as scRNAseq profiles of human fetal gut derived organoids we describe embryonic and fetal epithelium composition, trace their differentiation dynamics and signaling partners, and provide links to regenerating Crohn’s disease epithelium.

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