Epigenetic landscape reveals MECOM as an endothelial lineage regulator

Lv, Jie; Meng, Shu; Gu, Qilin; Zheng, Rongbin; Gao, Xinlei; Kim, Jun Dae; Chen, Min; Xia, Bo; Zuo, Yi-Han; Zhu, Sen; Zhao, Dongyu; Li, Yanqiang; Wang, Guangyu; Wang, Xin; Meng, Qingshu; Cao, Qi; Cooke, John P.; Fang, Longhou; Chen, Kaifu; Zhang, Lili

doi:10.1038/s41467-023-38002-w

Cited by 16 publications

(15 citation statements)

References 68 publications

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“…This finding was consistent with Vitronectin-integrin signaling being a crucial causal contributor to mouse angiogenesis 101 . Moreover, the depletion of Mecom , an endothelial cell lineage regulator and one of the target genes, has further been shown to impair Zebrafish angiogenesis 102 . Following the same strategy, we also interrogated the Shh combined interaction GP, enriched in the Floor Plate niche ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Quantitative characterization of cell niches in spatial atlases

Birk,

Bonafonte-Pardàs,

Feriz

et al. 2024

Preprint

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Spatial omics holds great potential to elucidate tissue architecture by dissecting underlying cell niches and cellular interactions. However, we lack an end-to-end computational framework that can effectively integrate different spatial omics tissue samples, quantitatively characterize cell niches based on biological knowledge of cell-cell communication and transcriptional regulation pathways, and discover spatial molecular programs of cells. We present NicheCompass, a graph deep learning method designed based on the principles of cellular communication. It utilizes existing knowledge of inter- and intracellular interaction pathways to learn an interpretable latent space of cells across multiple tissue samples, enabling the construction and querying of spatial reference atlases. NicheCompass learns the activity of an interaction pathway by modeling the process through the lens of cells receiving and processing signals from their tissue microenvironment, using a variety of mechanisms involving metabolic interactions, ligand-receptor interactions including downstream regulation, and regulons. In addition to leveraging existing knowledge, NicheCompass can learn novel spatially variable gene programs to model variation in the tissue. We showcase a comprehensive workflow encompassing data integration, niche identification, and functional interpretation, and demonstrate that NicheCompass outperforms existing approaches. NicheCompass is broadly applicable to spatial transcriptomics data, which we illustrate by mapping the architecture of diverse tissues during mouse embryonic development, and delineating basal (KRT14) and luminal (KRT8) tumor cell niches in human breast cancer. Moreover, we introduce fine-tuning-based spatial reference mapping, revealing an SPP1+ macrophage-dominated tumor microenvironment in non-small cell lung cancer patients. We further extend NicheCompass to multimodal spatial profiling of gene expression and chromatin accessibility, identifying distinct white matter niches in the mouse brain. Finally, we apply NicheCompass to a whole mouse brain spatial atlas with 8.4 million cells across 239 tissue sections from four mice, demonstrating its ability to build foundational, interpretable spatial representations for entire organs. Overall, NicheCompass provides a novel end-to-end workflow for analyzing large-scale spatial omics data.

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Section: Resultsmentioning

confidence: 99%

Quantitative characterization of cell niches in spatial atlases

Birk,

Bonafonte-Pardàs,

Feriz

et al. 2024

Preprint

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“…The gene is upregulated in HE1 but is then sharply down-regulated (Fig 5A,B). It has recently been shown to be essential for the development of endothelial cells (Lv et al, 2023). It contains an enhancer located at +340 kb which is primed in HB but when examined in isolation does not show high enhancer activity in our reporter assay until the HE1 state (Fig 5C).…”

Section: Resultsmentioning

confidence: 99%

“…We identified multiple VEGF regulated priming elements associated with the activation of hematopoietic genes such as Spi1 (PU.1) C , sf3r or BC11a at the HP stage. An important VEGF-responsive gene is Mecom which is transcriptionally activated at the HE stage and is a major regulator for endothelial cell development(Lv et al, 2023). Our work shows that its +340 kb enhancer element which is primed at the HB stage is crucial for the tissue-specific activation of this gene.…”

Section: Discussionmentioning

confidence: 99%

“…Here, the activation of gene expression at the HE1 stage is reduced until the GRN has passed a threshold that brings the other enhancers online and the proportion of HP cells within the population catches up (albeit at reduced numbers). It has been shown that Mecom expression is crucial for the expression of VEGFR2 which is a major receptor for VEGF signaling(Lv et al, 2023) thus setting up a feed forward loop that provides a molecular explanation for this result. A similar phenomenon was seen when the Spi1 (PU.1) −14 URE was mutated by eliminating a PU.1 autoregulatory binding site, upregulation of gene expression was delayed until additional enhancers were activated (Lichtinger et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification

Maytum,

Edginton-White,

Keane

et al. 2023

Preprint

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Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating each of five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated prior to the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the upregulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control.

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“…1d and Extended Data Fig. 2a,b), which are commonly recognized as markers or key regulators for adult stem cells [39][40][41][42][43][44][45] . Additionally, Stem1 cells are rich in CMZ marker genes, notably ZIC1, alongside critical genes such as CPAMD8, MEIS1and TGFβ2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification and characterization of human retinal stem cells capable of retinal regeneration

Su,

Liu,

et al. 2023

Preprint

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Human retinal stem cells hold great promise in regenerative medicine, yet their existence and characteristics remain elusive. Here, we preformed single-cell multi-omics and spatial transcriptomics of human fetal retinas and uncovered a novel cell subpopulation, human neural retinal stem-like cells (hNRSCs), distinct from RPE stem-like cell and traditional retinal progenitor cells. These hNRSCs reside in the peripheral retina within the ciliary marginal zone, exhibiting substantial self-renewal and differentiation potential. We conducted single-cell and spatial transcriptomic analysis of human retinal organoids (hROs), and revealed hROs have remarkable similar hNRSCs consistent with fetal retina, capable of regenerating all retinal cells. Furthermore, we identified crucial transcription factors, notably MECOM, governing hNRSC commitment to neural retinogenesis and regulating hROs regeneration. Transplanting hRO-derived hNRSCs into the rd10 mouse of rapid retinal degeneration significantly repairs the degenerated retina and restores visual function. Together, our work identifies and characterizes a unique category of retinal stem cells from human retinas, underscoring their regenerative potential and promise for transplantation therapy.

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Epigenetic landscape reveals MECOM as an endothelial lineage regulator

Cited by 16 publications

References 68 publications

Quantitative characterization of cell niches in spatial atlases

Quantitative characterization of cell niches in spatial atlases

Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification

Identification and characterization of human retinal stem cells capable of retinal regeneration

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