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DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate

ABSTRACT: DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate

PROVIDER: PRJNA530392 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8835680_1.fastq.gz	Fastqsanger.gz
	SRR8835680_2.fastq.gz	Fastqsanger.gz
	SRR8835681_1.fastq.gz	Fastqsanger.gz
	SRR8835681_2.fastq.gz	Fastqsanger.gz
	SRR8835682_1.fastq.gz	Fastqsanger.gz

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DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate

Project description:Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.

2020-01-24 | GSE129177 | GEO

Dnmt1 is required for proximal-distal patterning of the lung endoderm and for restraining alveolar type 2 cell fate.

Project description:Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.

| S-EPMC6822389 | biostudies-literature

Emergence and patterning dynamics of mouse definitive endoderm

Project description:Emergence and patterning dynamics of mouse definitive endoderm

| PRJNA782003 | ENA

Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Expression data set]

2013-11-07 | GSE52158 | GEO

Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Expression data set]

Project description:The definitive endoderm germ layer is the provenance of multiple internal organs, including the lungs, liver, pancreas and intestines. Molecular events driving initial endoderm germ layer specification and subsequent anterior-posterior patterning of endoderm into distinct organ primordia remain largely cryptic. Through microarray analyses, we captured genome-wide transcriptional dynamics driving successive stages of endoderm development with the intent of identifying novel regulatory genes or diagnostic markers that respectively drive or mark endoderm committment. HES3 human embryonic stem cells (hESCs) were differentiated into highly homogeneous endodermal progenitor populations, and microarray analyses were conducted of six different populations at different tiers of the endodermal lineage hierarchy: undifferentiated hESCs, anterior primitive streak (day 1 of in vitro differentiation), definitive endoderm (day 3) and anterior foregut, posterior foregut or midgut/hindgut patterned endoderm populations (day 7). Additionally, we compared hESCs differentiated using two alternative endoderm induction protocols, serum-based or AFBLy-based differentiation (both day 3 of differentiation).

2013-11-07 | E-GEOD-52158 | biostudies-arrayexpress

Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Endoderm RNA-seq and ChIP-seq data sets]

Project description:Unraveling complex signaling programs animating developmental lineage-decisions is pivotal to differentiate human pluripotent stem cells (hPSC) into pure populations of desired lineages for regenerative medicine. Developmental signals are strikingly temporally dynamic: BMP and Wnt initially specify primitive streak (progenitor to endoderm) yet 24 hours later suppress endoderm and induce mesoderm. At lineage bifurcations we show mutually-exclusive embryonic lineages are segregated through cross-repressive signals: TGFM-NM-2 and BMP/MAPK duel to respectively specify pancreas versus liver from endoderm. Unilateral endodermal differentiation requires blockade of alternative fates at every stage, revealing a universal developmental strategy for efficient differentiation and anterior-posterior patterning of diverse hPSC lines into highly-pure endodermal populations. This culminated in hPSC-derived hepatic progenitors that, for the first time, engraft long-term in genetically-unconditioned mouse livers and secrete human albumin. Finally, thirty transcriptional and chromatin state maps capturing endoderm commitment revealed endodermal enhancers reside in an unanticipated diversity of "pre-enhancer" chromatin states before activation. Endoderm RNA-seq and ChIP-seq data sets

2013-11-22 | E-GEOD-52657 | biostudies-arrayexpress

Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Endoderm RNA-seq and ChIP-seq data sets]

Project description:Unraveling complex signaling programs animating developmental lineage-decisions is pivotal to differentiate human pluripotent stem cells (hPSC) into pure populations of desired lineages for regenerative medicine. Developmental signals are strikingly temporally dynamic: BMP and Wnt initially specify primitive streak (progenitor to endoderm) yet 24 hours later suppress endoderm and induce mesoderm. At lineage bifurcations we show mutually-exclusive embryonic lineages are segregated through cross-repressive signals: TGFβ and BMP/MAPK duel to respectively specify pancreas versus liver from endoderm. Unilateral endodermal differentiation requires blockade of alternative fates at every stage, revealing a universal developmental strategy for efficient differentiation and anterior-posterior patterning of diverse hPSC lines into highly-pure endodermal populations. This culminated in hPSC-derived hepatic progenitors that, for the first time, engraft long-term in genetically-unconditioned mouse livers and secrete human albumin. Finally, thirty transcriptional and chromatin state maps capturing endoderm commitment revealed endodermal enhancers reside in an unanticipated diversity of "pre-enhancer" chromatin states before activation.

2013-11-22 | GSE52657 | GEO

Emergence and patterning dynamics of mouse definitive endoderm

Project description:The segregation of definitive endoderm (DE) from bi-potent mesendoderm progenitors leads to the formation of two distinct germ layers. Dissecting DE commitment and onset has been challenging as it occurs within a narrow spatio-temporal window in the embryo. Here we employ a novel dual Bra/Sox17 reporter cell line to study DE onset dynamics. We find Sox17 expression initiates in a few isolated cells in vivo within a temporally restricted window. Using 2D and 3D in vitro models, we show that DE cells emerge from mesendoderm progenitors at a temporally regular, but spatially stochastic pattern, which is subsequently arranged by self-sorting of Sox17+ cells. A subpopulation of Bra-high cells commits to a Sox17+ fate independent of external Wnt signal. Self-sorting coincides with up-regulation of E-cadherin but is not necessary for DE differentiation or proliferation. Our in vivo and in vitro results highlight basic rules governing DE onset and patterning through the commonalities and differences between these systems.

2021-12-13 | GSE189224 | GEO

Distal-to-Proximal Re-patterning of Small Airway Epithelium in Smoking-associated Chronic Obstructive Pulmonary Disease

Project description:The proximal-distal patterning program determines unique structural and functional properties of proximal and distal airways in the adult lung. Based on the knowledge that remod-eling of distal airways is the major pathologic feature of chronic obstructive pulmonary disease (COPD), and that small airway epithelium (SAE), which covers distal airways, is the primary site of the initial smoking-induced changes relevant to COPD pathogenesis, we hypothesized that in COPD smokers, the SAE transcriptome loses its region-specific biologic identity and takes on the transcriptional pattern of the proximal airways. By analyzing human airway epithelium col-lected by bronchoscopic brushings from proximal and distal airways of healthy smokers, proxi-mal and distal airway epithelial transcriptome signatures were identified. Dramatic smoking-dependent suppression of distal signature paralleled by acquisition of the proximal airway epithe-lial phenotype was found in the SAE of COPD smokers. Distal-proximal re-patterning observed in the SAE of smokers in vivo was reproduced in vitro by stimulating SAE basal cells (BC), the stem/progenitor cells of the SAE, with EGF, a growth factor up-regulated in airway epithelium by smoking. Together, this study identifies distal-proximal SAE re-patterning as a characteristic feature of small airway disordering in COPD smokers potentially driven by EGF/EGFR-mediated reprogramming of SAE BC stem/progenitor cells.

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Transcriptional remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm [ATAC-seq]

Project description:Transcriptional remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm [ATAC-seq]

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