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The Unfolded Protein Response Regulator, ATF6, Promotes Mesodermal Differentiation

ABSTRACT: ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of ATF6α and its paralog ATF6β, results in embryonic lethality, notochord dysgenesis, and in people, loss of ATF6α specifically, results in malformed neuroretina and congenital vision loss. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated the function of ATF6 in development using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a recently identified small molecule ATF6 agonist, and we inhibited ATF6 using iPSCs from patients harboring ATF6 mutations. We discovered that ATF6 suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. Our findings reveal a novel role for ATF6 during differentiation and identify a new strategy to robustly create mesodermal tissues through modulation of the ATF6 arm of the UPR.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106847 | GEO | 2017/11/14

SECONDARY ACCESSION(S): PRJNA418171

REPOSITORIES: GEO

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ATF6 is required for the survival of castration-resistant prostate cancer cells

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The Unfolded Protein Response Regulator, ATF6, Promotes Mesodermal Differentiation

Project description:The Unfolded Protein Response Regulator, ATF6, Promotes Mesodermal Differentiation

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ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Project description:Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at transcriptional levels. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells (hESCs), resulted in premature cellular aging, characteristic of loss of endomembrane homeostasis. Comparative transcriptomic analyses in hMSCs identify 145 constitutive and 112 tunicamycin-induced ATF6-regulated genes implicated in different layers of cellular homeostasis regulation. Notably, FOS was identified as one of the constitutive ATF6 responsive genes, downregulation of which contributes to accelerated hMSC senescence. Our study identifies a novel transcriptional program related to homeostatic regulation of membrane organelles, and provides mechanistic insights into aging-associated attrition of human stem cells.

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2012-01-02 | E-GEOD-33515 | biostudies-arrayexpress

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

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