“Stripe” transcription factors provide accessibility to co-binding partners in mammalian genomes

Zhao, Yongbing; Vartak, Supriya V.; Conte, A.; Wang, Xiang; Garcia, David A.; Stevens, Evan; Jung, Seol Kyoung; Kieffer-Kwon, Kyong-Rim; Vian, Laura; Stodola, Timothy J.; Morís, Francisco; Chopp, Laura B.; Preite, Silvia; Schwartzberg, Pamela L.; Kulinski, Joseph M.; Olivera, Ana; Harly, Christelle; Bhandoola, Avinash; Heuston, Elisabeth F.; Bodine, David M.; Urrutia, Raúl; Upadhyaya, Arpita; Weirauch, Matthew T.; Hager, Gordon L.; Casellas, Rafael

doi:10.1016/j.molcel.2022.06.029

Cited by 32 publications

(41 citation statements)

References 94 publications

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“…Despite the important role of these factors during early gonadal development, our results suggest a fundamental difference in their mechanism of action, with WT1 acting as a gonad-specific stripe factor that renders the chromatin accessible. This tissue-restricted function contrasts with the widespread effects described for other universal stripe factors, like those belonging to the SP/KLF family 34 .…”

Section: Discussioncontrasting

confidence: 77%

“…Furthermore, this analysis revealed a common enrichment in GC-rich motifs, such as PATZ1 or members of the Specificity-Protein/Krüppel-like factor (SP/KLF) family. Interestingly, this group of TFs render chromatin accessible to other TFs 34 . In addition, other TF motifs resulted in increased connectivity in specific samples, such as PBX3 in female bipotential cells.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, AP-1 has been previously shown to mediate 3D regulatory hubs in differentiation processes 39,40 , which is consistent with the increased transcriptional response at the onset of Sertoli cell differentiation, in comparison to granulosa cells 19,37,38 . We further explored the combinatorial nature of TF interaction during sex determination by examining the colocalization of binding motifs within ATAC-seq footprints 34 . The analysis revealed that several TF act as “stripe factors”, which may increase chromatin accessibility for other co-binding TF partners 34 ( Fig 3c; Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We further explored the combinatorial nature of TF interaction during sex determination by examining the colocalization of binding motifs within ATAC-seq footprints 34 . The analysis revealed that several TF act as “stripe factors”, which may increase chromatin accessibility for other co-binding TF partners 34 ( Fig 3c; Extended Data Fig. 11 ).…”

Section: Resultsmentioning

confidence: 99%

“…Our results suggest a three-step model for mammalian sex determination. First, TFs with high affinity for GC-rich sequences, such as members of the SP/KLF family, may remodel chromatin and create an accessible environment for other co-binding partners 34 . As these factors recognize very similar motifs, they might act cooperatively to increase chromatin accessibility through assisted loading 55 .…”

Section: Discussionmentioning

confidence: 99%

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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Mota-Gómez

Rodríguez

Dupont

et al. 2022

Preprint

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Mammalian sex is determined by an opposing networks of ovarian and testicular genes that are well characterized. However, its epigenetic regulation is still largely unknown, thus limiting our understanding of a fundamental process for species propagation. Here we explore the 3D chromatin landscape of sex determination in vivo, by profiling FACS-sorted embryonic mouse gonadal populations, prior and after sex determination, in both sexes. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis that identifies 3D enhancer hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the enhancer hubs of hundreds of genes that display temporal- and sex-specific expression. Moreover, the identification of the 3D enhancer hubs allows the reconstruction of regulatory networks, revealing key transcription factors involved in sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, deletion of which results in male-to-female sex reversal with the upregulation of ovarian-specific markers and the initiation of meiosis. Thus, spatial auto-correlation analysis is an effective strategy to identify regulatory networks associated to biological processes and to further characterize the functional role of the 3D genome.

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Section: Discussioncontrasting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Mota-Gómez

Rodríguez

Dupont

et al. 2022

Preprint

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Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6

Guimarães,

Barrios,

de Oliveira

et al. 2024

J cachexia sarcopenia muscle

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BackgroundThe maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology in vivo and in vitro.MethodsGlobal RNA‐seq was performed in Nr2f6 knockdown C2C12 myocytes (N = 4–5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (N = 3–6). Nr2f6 content was evaluated in lipid overload models in vitro and in vivo (N = 3–6). In vivo experiments included Nr2f6 overexpression in mouse tibialis anterior muscle, followed by gene array transcriptomics and molecular assays (N = 4), ex vivo contractility experiments (N = 5), and histological analysis (N = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice.ResultsNr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle‐related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two‐fold to three‐fold) and siRNA‐mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid‐induced cell death. Nr2f6 content decreased by 40% in lipid‐overloaded myotubes and by 50% in the skeletal muscle of mice fed a high‐fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation‐like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC‐1α (30%) promoters activity following Nr2f6 overexpression in vitro. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation.ConclusionsOur findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies.

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MSC-derived exosomes deliver ZBTB4 to mediate transcriptional repression of ITIH3 in astrocytes in spinal cord injury

Wu,

Wang,

Liao

et al. 2024

Brain Research Bulletin

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“Stripe” transcription factors provide accessibility to co-binding partners in mammalian genomes

Cited by 32 publications

References 94 publications

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6

MSC-derived exosomes deliver ZBTB4 to mediate transcriptional repression of ITIH3 in astrocytes in spinal cord injury

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