Sin3a regulates epithelial progenitor cell fate during lung development

Yao, Changfu; Carraro, Gianni; Konda, Bindu; Guan, Xiangrong; Mizuno, Takako; Chiba, Norika; Kostelny, Matthew; Kurkciyan, Adrianne; Gourichon, David; McQualter, Jonathan L.; Stripp, Barry R.

doi:10.1242/dev.149708

Cited by 31 publications

(27 citation statements)

References 57 publications

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“…Taken together, Sin3a likely regulates gene expression through both Hdac1/2-dependent and -independent mechanisms. In agreement with our findings, Sin3a deletion leads to a more severe defect in lungs relative to deletion of Hdac1/2, and there is only partial overlap of transcriptome changes between them (48,49).…”

Section: Discussionsupporting

confidence: 93%

Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdacl

Zhao¹,

Li²,

Wang³

et al. 2019

FASEB j.

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Suppressor interacting 3a (Sin3a) is a scaffold component of the chromatin repressive complex Sin3/histone deacetylase (Hdac). Sin3a has been shown as a hub gene driving preimplantation development in both mice and humans. However, its precise functions during preimplantation development remain unclear. Here, we show that the embryos arrested at morula stage upon specific depletion of Sin3a in mouse early embryos. Given the reduced cell number in Sin3a‐depleted embryos, blocked cell proliferation is observed, likely because of the increased level of Trp53 acetylation at lysine 379. Moreover, we found that Sin3a depletion reduces Cdx2 and Tir Na Nog (Nanog), suggesting a failure of the first cell fate decision. In addition, we noted a striking increase of genome‐wide DNA methylation, likely attributed to the increased nuclear DNA methyltransferase 1 observed in Sin3a‐depleted embryos. Notably, RNA sequencing analyses showed 717 genes are differentially expressed, and Gene Ontology analysis of down‐regulated genes (e.g., Hdac1) revealed top enriched terms involving protein deacetylation. Consistently, we confirmed a significant decrease of Hdac1 mRNA and protein abundance. Importantly, the development and Trp53 acetylation in Sin3a‐depleted embryos could be rescued by expression of Hdac1 but not Hdac2. In summary, our results indicate a vital role of Sin3a in safeguarding the developmental progression through the morula‐to‐blastocyst transition via Hdacl.—Zhao, P., Li, S., Wang, H., Dang, Y., Wang, L., Liu, T., Wang, S., Li, X., Zhang, K. Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdac1. FASEB J. 33, 12541–12553 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdacl

Zhao¹,

Li²,

Wang³

et al. 2019

FASEB j.

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“…We next sought to determine whether senescence of AT2 cells drives progressive fibrosis. In our previous work, we demonstrated that endodermal progenitor cells of the developing mouse lung are uniquely dependent upon Sin3a and that loss of Sin3a in developmental endodermal progenitor cells leads to senescence and aberrant lung development (37). To determine if the progenitor function of adult lung AT2 cells have a similar dependence on Sin3a, we generated Sftpc CreER ; Sin3a f/f ; Rosa mTmG to allow tamoxifen-induced conditional Sin3a loss-of-function (LOF) in AT2 cells (herein referred to as Sin3a-LOF; Fig 2A).…”

Section: A Novel Mouse Model Of Conditional At2 Stem Cell Senescencementioning

confidence: 99%

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Yao

Guan

Carraro

et al. 2019

Preprint

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Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfb activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfb activation, block fibrogenesis.

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“…The authors linked the phenotype to up-regulation of c-Myc genes due to reduced Mxd-family repression via Sin3A and enhanced DNA damage. Finally, Sin3A plays a critical role during lung development, as loss of activity in the early foregut endoderm of the developing mouse leads to widespread defects and neonatal death [105]. Defects included down-regulation of endodermal genes and induction of a senescent-like state, consistent with up-regulation of cell cycle inhibitors p16 and p21, further supporting the role of Sin3A in cell cycle regulation.…”

Section: Sin3 In Tissue Developmentmentioning

confidence: 93%

Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex

Adams

Chandru

Cowley

2018

Biochemical Journal

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At face value, the Sin3 histone deacetylase (HDAC) complex appears to be a prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression. While this is almost certainly part of its role, Sin3 stubbornly refuses to be pigeon-holed in quite this way. Genome-wide mapping studies have found that Sin3 localises predominantly to the promoters of actively transcribed genes. While Sin3 knockout studies in various species result in a combination of both up- and down-regulated genes. Furthermore, genes such as the stem cell factor, Nanog, are dependent on the direct association of Sin3 for active transcription to occur. Sin3 appears to have properties of a co-repressor, co-activator and general transcription factor, and has thus been termed a co-regulator complex. Through a series of unique domains, Sin3 is able to assemble HDAC1/2, chromatin adaptors and transcription factors in a series of functionally and compositionally distinct complexes to modify chromatin at both gene-specific and global levels. Unsurprisingly, therefore, Sin3/HDAC1 have been implicated in the regulation of numerous cellular processes, including mammalian development, maintenance of pluripotency, cell cycle regulation and diseases such as cancer.

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Sin3a regulates epithelial progenitor cell fate during lung development

Cited by 31 publications

References 57 publications

Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdacl

Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdacl

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex

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