Sin3a regulates epithelial progenitor cell fate during lung development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE94306 | GEO | 2017/06/22
SECONDARY ACCESSION(S): PRJNA369296
REPOSITORIES: GEO
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Project description:Congenital diaphragmatic hernia (CDH) is a common and severe congential malformation characterized by defects in diaphragm, lung, and pulmonary vascular developent. Despite the frequency and severity of CDH, the underlying developmental mechanisms are not understood. We identified SIN3A loss of function sequence variants in two patients with CDH. To understand the genetic and developmental mechanisms of CDH, we generated Sin3a conditional knockout mice that lack Sin3a expression in the lung mesenchyme. SIN3A plays a critcal role during development, directing cell lineage specification and cell cycling. Despite this role, SIN3A sequence variants have not been reported in patients with CDH or other congential malformations. We found that Sin3a CKO mice have abnormal lung stucture at birth into adulthood. To determine the role of Sin3a in lung mesenchymal development, we performed transcriptomic analysis of Sin3a CKO and control lungs at embryonic day 16 (E16) when cell cycling defects were first evident, postnatal day 0 (P0) when lung defects were first evident, and P3 when lung phenotyopes worsened. In this dataset are expression data from dissected embryonic and postnatal lungs of Sin3a CKO and control mice. Sin3a CKO mice have conditional deletion of Sin3a in the lung mesenchyme directed by Tbx4rtta; tetocre (Tbx4rtta; tetocre; Sin3a flox/flox CKO). Control mice are heterozygous for Sin3a in the lung mesenchyme (Tbx4rtta; tetocre; Sin3a flox/WT). These data were used to identify transcriptional changes due to loss of Sin3a in the lung mesenchyme.
2023-12-31 | GSE246305 | GEO
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Project description:Congenital diaphragmatic hernia (CDH) is a common and severe congential malformation characterized by defects in diaphragm, lung, and pulmonary vascular developent. Despite the frequency and severity of CDH, the underlying developmental mechanisms are not understood. We identified SIN3A loss of function sequence variants in two patients with CDH. To understand the genetic and developmental mechanisms of CDH, we generated Sin3a conditional knockout mice that lack Sin3a expression in the lung mesenchyme. SIN3A has been shown to play a critcal role during development, directing cell lineage specification and cell cycling. We found mesenchymal progenitor cells in Sin3a CKO mice have altered expression of cell cycle progression genes from bulk lung transcriptomic analysis. To investigate changes in gene expression that occur specifically in lung mesenchymal cells, we performed fluorescent activated cell sorting (FACS) to isolate cells that underwent recombination of Sin3a. We then performed transcriptomic analysis on sorted mesenchymal cells from embryonic day 16 (E16) Sin3a CKO and control lungs. In this dataset are expression data from FACS-isolated recombined lung mesenchymal cells of Sin3a CKO and control mice. Sin3a CKO mice have conditional deletion of Sin3a in the lung mesenchyme directed by Tbx4rtta; tetocre (Tbx4rtta; tetocre; Sin3a flox/flox CKO). Control mice are heterozygous for Sin3a in the lung mesenchyme (Tbx4rtta; tetocre; Sin3a flox/WT). These data were used to identify transcriptional changes due to loss of Sin3a in the lung mesenchyme.
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Project description:Congenital diaphragmatic hernia (CDH) is a common and severe congential malformation characterized by defects in diaphragm, lung, and pulmonary vascular developent. Despite the frequency and severity of CDH, the underlying developmental mechanisms are not understood. We identified SIN3A loss of function sequence variants in two patients with CDH. To understand the genetic and developmental mechanisms of CDH, we generated Sin3a conditional knockout mice that lack Sin3a expression in the lung mesenchyme. SIN3A has been shown to play a critcal role during development, directing cell lineage specification and cell cycling. We found that loss of SIN3A resulted in impaired mesenchymal cell differentiation from bulk lung transcriptomic analysis in Sin3a CKO mice. To investigate the impact of loss of SIN3A in mesenchymal cell differentation, we performed fluorescent activated cell sorting (FACS) to isolate cells that underwent recombination of Sin3a. We then performed single-cell transcriptomic analysis on sorted mesenchymal cells from embryonic day 16 (E16) Sin3a CKO and control lungs. In this dataset are expression data from FACS-isolated recombined lung mesenchymal cells of Sin3a CKO and control mice. Sin3a CKO mice have conditional deletion of Sin3a in the lung mesenchyme directed by Tbx4rtta; tetocre (Tbx4rtta; tetocre; Sin3a flox/flox CKO). Control mice are heterozygous for Sin3a in the lung mesenchyme (Tbx4rtta; tetocre; Sin3a flox/WT). These data were used to identify transcriptional changes due to loss of Sin3a in the lung mesenchyme.
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Project description:Sin3a is the central scaffold protein of the prototypical Hdac1/2 chromatin repressor complex, crucially required during early embryonic development for the growth of pluripotent cells of the inner cell mass. Here, we explore the endogenous composition of the Sin3a-Hdac complex in pluripotent embryonic stem (ES) and differentiated cells. To do this, we established an endogenous double immunoprecipitation strategy coupled with quantitative mass spectrometry (ENDIP-MS) allowing us to define the precise composition of the Sin3a complex in multiple cell types. We identify the Fam60a subunit as a key defining feature of a variant Sin3a complex present in ES cells, but not in differentiated cells. Fam60a co-occupies H3K4me3 positive promoters with Sin3a and is essential to maintain it on chromatin. Consistent with this, Fam60a depletion phenocopies the loss of Sin3a, leading to decreased proliferation, an extended G1-phase and the deregulation of genes associated with differentiation. Taken together, our data characterise Fam60a as an essential core subunit of a variant Sin3a complex in ES cells required to promote rapid proliferation and to prevent unscheduled differentiation.
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