Chd4 remodels chromatin to control retinal cell type specification and lineage termination
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ABSTRACT:
PROVIDER: PRJNA1279178 | ENA |
REPOSITORIES: ENA
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Project description:During development, neural progenitor cells modify their output over time to produce different types of neurons and glia in chronological sequences. Previous studies have shown that epigenetic processes play a crucial role in regulating neural progenitor potential, but the underlying mechanisms are not well understood. Here, we hypothesized that nucleosome remodelling would regulate the competence transitions of retinal progenitors. We generated retina-specific conditional knockouts (cKOs) in the key nucleosome remodelling enzyme Chd4. Chd4 cKOs overproduced early-born retinal ganglion and amacrine cells. Postnatally, later-born rod photoreceptors were drastically underproduced. Concomitantly, progenitors failed to be exhausted at late phases of development and ultimately overproduced Müller glia. To determine how Chd4 regulates the genome, we used cut&run-seq to reveal Chd4 genome occupancy, and ATAC-seq experiments to visualize nucleosome remodelling. These data revealed that genome accessibility was significantly increased at ∼10,000 regulatory elements and ∼4,000 genes in the Chd4 cKO. Together, these results suggest that Chd4 restricts the genome to repress progenitor identity and promote rod photoreceptor production. Accordingly, multiplexed single-cell transcriptomics demonstrated that deletion of Chd4 led to markedly divergent gene expression profiles. However, despite overproduction of early fates and underproduction of later-born rods, the perinatal transition between early and late progenitor competence was not altered as determined by birthdating experiments and transcriptomic signatures. Taken together, our data suggest that Chd4-dependent chromatin remodelling regulates cell fate specification, and is also required to terminate retinal neurogenesis, but that it does not regulate the progenitor competence windows that restrict early-vs. late-cell-type production.
2025-09-02 | GSE300175 | GEO
Project description:During retinal development, neurons and glia are produced in a highly stereotyped and evolutionarily conserved birth order. Landmark studies have demonstrated that the sequence of cell production is temporally encoded. Transcription factors and heterochromatic determinants have been elsewhere implicated in the temporal regulation of progenitor competence states, but the underlying mechanisms are not well understood. Since chromatin remodelling complexes interact with both transcription factors and heterochromatic complexes such as polycomb, we focused on the nucleosome remodeller Chd4. We generated conditional knockouts (cKOs) of Chd4 – a key chromatin remodelling enzyme in neural progenitors. Chd4 cKOs exhibited a marked expansion in early-born retinal ganglion cells. Postnatally, rod photoreceptors were drastically underproduced. As a result, progenitors failed to be exhausted during late phases of development, leading to a striking increase in the production of Müller glia. Clonal retroviral lineaging and histological marker analyses suggest that these effects were independent of alterations in cell death or proliferation. Next, we examined the effect of Chd4 on the genome and transcriptome, focusing on retinal progenitors at P0/P1. Multi-seq single-cell transcriptomics demonstrated that deletion of Chd4 created divergent gene expression profiles and developmental trajectories. ATAC-seq experiments performed on sorted P1 retinal progenitors revealed that chromatin accessibility was significantly increased at ~10 000 enhancer elements and ~4000 genes in the Chd4 cKO, demonstrating that Chd4 is required to repress gene expression and genome accessibility. Finally, to determine whether Chd4 regulates retinal cell-type production by altering competence windows, we performed EdU birthdating. These experiments revealed that cell fates were altered without affecting competence windows. Thus, despite a very strong shift in the production of early-born and late-born cell types, our data suggest that chromatin remodelling does not directly regulate competence windows.
2025-05-31 | GSE266039 | GEO
Project description:Multiple myeloma (MM) is an incurable hematologic malignancy, which is inherently related to chromatin abnormalities. Chromatin remodeling factors play an important role in the regulation of chromatin abnormalities, among which chromodomain-helicase-DNA-binding protein 4 (CHD4) was positive-associated with poor outcomes in MM patients and an elevated level of CHD4 promoted MM cell proliferation. Mechanistically, CHD4 untwisted c-Myc G4 and regulated chromatin accessibility through ATPase domain. Additionally, CHD4 recruited c-Myc though chromatin domain and stabilized c-Myc to chromatin by liquid–liquid phase separation, which up-regulated the expression of c-Myc. Furthermore, Luteolin 7-O-glucuronide and Idarubicin were identified as potential drugs targeting ATPase domain and chromatin domain for MM by a de novo design. Our study highlights the role of CHD4 as a high-risk gene in MM and suggests that remodels cellular chromatin accessibility and activates c-Myc pathway via phase separation in MM.
2024-12-25 | GSE285112 | GEO
Project description:To investigate whether there is a physiological interaction between CHD4 and c-Myc, we conducted MS and found that CHD4 interacted with c-Myc.
2024-12-12 | PXD058803 |
Project description:Retinoic acid (RA) is a key morphogen in human retinal development, activating transcriptional programs that drive retinal progenitor differentiation and photoreceptor development, ensuring proper spatial organisation within the neural retina, essential for vision. Despite its well-established role in retinal patterning, the concentration-dependent effects of RA on human retinal cell fate specification and the regional definition of the primate macula and peripheral retina remain poorly understood. Here, we show that temporal and dosage-dependant modulation of RA during human retinal organoid differentiation induces distinct changes in retinal cell abundance, maturation, and organisation. Single-cell transcriptomics and protein analysis revealed that RA dosage influenced the relative abundance and maturation of photoreceptors and retinal interneurons. Spatial transcriptomics analyses demonstrated that low RA levels biased retinal organoids toward a macular-like regional identity, whereas high RA levels promoted peripheral-like development. Collectively, our findings emphasise the critical role of RA signalling in retinal maturation and regional specification. This study elucidates mechanisms involved in human retinal development and we anticipate that controlled RA modulation in retinal organoids provides a strategy to refine disease modelling of inherited retinal disorders and enhance the specific generation of photoreceptors suitable for transplantation and regenerative therapies.
2026-03-22 | GSE293582 | GEO
Project description:The Chd4 chromatin remodeller controls temporal programs during retinal neurogenesis
| PRJNA1105560 | ENA
Project description:Retinoic acid (RA) is a key morphogen in human retinal development, activating transcriptional programs that drive retinal progenitor differentiation and photoreceptor development, ensuring proper spatial organisation within the neural retina, essential for vision. Despite its well-established role in retinal patterning, the concentration-dependent effects of RA on human retinal cell fate specification and the regional definition of the primate macula and peripheral retina remain poorly understood. Here, we show that temporal and dosage-dependant modulation of RA during human retinal organoid differentiation induces distinct changes in retinal cell abundance, maturation, and organisation. Single-cell transcriptomics and protein analysis revealed that RA dosage influenced the relative abundance and maturation of photoreceptors and retinal interneurons. Spatial transcriptomics analyses demonstrated that low RA levels biased retinal organoids toward a macular-like regional identity, whereas high RA levels promoted peripheral-like development. Collectively, our findings emphasise the critical role of RA signalling in retinal maturation and regional specification. This study elucidates mechanisms involved in human retinal development and we anticipate that controlled RA modulation in retinal organoids provides a strategy to refine disease modelling of inherited retinal disorders and enhance the specific generation of photoreceptors suitable for transplantation and regenerative therapies.
2026-03-22 | GSE293464 | GEO
Project description:Retinoic acid (RA) is a key morphogen in human retinal development, activating transcriptional programs that drive retinal progenitor differentiation and photoreceptor development, ensuring proper spatial organisation within the neural retina, essential for vision. Despite its well-established role in retinal patterning, the concentration-dependent effects of RA on human retinal cell fate specification and the regional definition of the primate macula and peripheral retina remain poorly understood. Here, we show that temporal and dosage-dependant modulation of RA during human retinal organoid differentiation induces distinct changes in retinal cell abundance, maturation, and organisation. Single-cell transcriptomics and protein analysis revealed that RA dosage influenced the relative abundance and maturation of photoreceptors and retinal interneurons. Spatial transcriptomics analyses demonstrated that low RA levels biased retinal organoids toward a macular-like regional identity, whereas high RA levels promoted peripheral-like development. Collectively, our findings emphasise the critical role of RA signalling in retinal maturation and regional specification. This study elucidates mechanisms involved in human retinal development and we anticipate that controlled RA modulation in retinal organoids provides a strategy to refine disease modelling of inherited retinal disorders and enhance the specific generation of photoreceptors suitable for transplantation and regenerative therapies.
2026-03-22 | GSE293457 | GEO
Project description:Atoh7-independent specification of retinal ganglion cell identity
| PRJNA658977 | ENA
Project description:Cell-lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage- and developmental stage-specific transcriptional programs. Accessibility and inaccessibility of gene loci are controlled dynamically during cellular development. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in early B cell progenitors in vivo, B cell progenitors are arrested at an early pro-B-like stage of development, unresponsive to IL-7 receptor signaling and complete V(D)J rearrangements at Igh loci inefficiently. Importantly, CHD4-deficient B cells express a significant number of non-B cell lineage genes, including genes involved in the development of other hematopoietic lineages and neuronal cells. The absence of CHD4 increased chromatin accessibility at hundreds of these gene loci, suggesting that its ability to repress transcription by mobilizing nucleosomes and compacting chromatin is a barrier against inappropriate transcription. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.
2019-04-30 | GSE123503 | GEO