Bidirectional Wnt signaling between endoderm and mesoderm confers tracheal identity in mouse and human cells

Kishimoto, Keishi; Furukawa, Kana T.; Luz-Madrigal, Agustín; Yamaoka, Akira; Matsuoka, Chisa; Habu, Masanobu; Alev, Cantas; Zorn, Aaron M.; Morimoto, Mitsuru

doi:10.1038/s41467-020-17969-w

Cited by 36 publications

(44 citation statements)

References 65 publications

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“…Gene expressions of both two tested pluripotency (Nanog and Oct4), mesoderm (Fgf8 and Brachyury), and imprinted (Tex19.1 and Dazl) marker genes were increased. The increase of mesoderm and imprinted mark genes was consistent with the elevated activation of Wnt signal-associated genes ( 53 , 54 ). Moreover, we assigned enhancers to the closest promoter within 500 Kb ( 52 ) and linked the enhancers into mesoderm, ectoderm, and trophectoderm markers genes as defined before ( 55 ).…”

Section: Resultssupporting

confidence: 63%

The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression

Fang

Tang

Zhang

et al. 2021

Nucleic Acids Research

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Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, leads to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It's known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we find that, when NSD1 is knocked out in mouse embryonic stem cells (mESCs), H3K27ac increases correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a ‘safeguard’, preventing further activation of active enhancer-associated genes.

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Section: Resultssupporting

confidence: 63%

The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression

Fang

Tang

Zhang

et al. 2021

Nucleic Acids Research

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“…The Wt1 -expressing coelomic epithelium contributes to the mature mesothelium, fibroblasts, stellate cells, smooth muscles, and white adipose tissue associated with the gastrointestinal tract, liver, lungs, urogenital system, and heart (Asahina et al, 2011; Cano et al, 2013; Carmona et al, 2016; Delgado et al, 2014; Lee et al, 2019; Lua et al, 2014; Martínez-Estrada et al, 2010; Rinkevich et al, 2012; Sebo et al, 2018; Zhou et al, 2008). Further, regional specification within the mesothelial components along the developing gut is recognizable early in mouse development (Han et al, 2020; Kishimoto et al, 2020). Studies using zebrafish have documented expression of wt1a/b, tcf21 , and tbx18 in the epicardium, the visceral mesothelial layer covering the heart (Peralta et al, 2013; Peralta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

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“…Future studies should clarify the physiological importance of temporal ERK activity dynamics in this process. In addition, further systematic investigations of other signaling pathways, such as Wnt and bone morphogenetic protein (Bmp) signaling (Snowball et al, 2015;Kishimoto et al, 2018), as well as physical interactions with epithelia and smooth muscles (Hines et al, 2013;Yin et al, 2018), would improve our understanding of tracheal development and in vitro organoid systems (Conway et al, 2020;Kishimoto et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development

Yoshida

Hirashima

2020

Front. Cell Dev. Biol.

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Tracheal cartilage provides architectural integrity to the respiratory airway, and defects in this structure during embryonic development cause severe congenital anomalies. Previous genetic studies have revealed genes that are critical for the development of tracheal cartilage. However, it is still unclear how crosstalk between these proteins regulates tracheal cartilage formation. Here we show a core regulatory network underlying murine tracheal chondrogenesis from embryonic day (E) 12.5 to E15.5, by combining volumetric imaging of fluorescence reporters, inhibitor assays, and mathematical modeling. We focused on SRY-box transcription factor 9 (Sox9) and extracellular signal-regulated kinase (ERK) in the tracheal mesenchyme, and observed a synchronous, inverted U-shaped temporal change in both Sox9 expression and ERK activity with a peak at E14.5, whereas the expression level of downstream cartilage matrix genes, such as collagen II alpha 1 (Col2a1) and aggrecan (Agc1), monotonically increased. Inhibitor assays revealed that the ERK signaling pathway functions as an inhibitory regulator of tracheal cartilage differentiation during this period. These results suggest that expression of the cartilage matrix genes is controlled by an incoherent feedforward loop via Sox9 and ERK, which is supported by a mathematical model. Furthermore, the modeling analysis suggests that a Sox9-ERK incoherent feedforward regulation augments the robustness against the variation of upstream factors. The present study provides a better understanding of the regulatory network underlying the tracheal development and will be helpful for efficient induction of tracheal organoids.

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Bidirectional Wnt signaling between endoderm and mesoderm confers tracheal identity in mouse and human cells

Cited by 36 publications

References 65 publications

The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression

The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development

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