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FAM122A is required for mesendodermal and cardiac differentiation of embryonic stem cells [ChIP-seq]

ABSTRACT: Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved house-keeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multi facet physiological and pathological processes, however, the in vivo function of FAM122A is largely unknown. In this study, we found that Fam122 deletion results in embryonic lethality with severe defects of cardiovascular developments and significantly attenuates the cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impairs mesendodermal specification and cardiac differentiation from mouse embryonic stem cells, but not influences the pluripotent identity. Mechanical investigation shows that the impaired differentiation potential is caused through the dysregulation of histone modification and Wnt and Hippo signaling pathways by modulating PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This not only significantly extends our understanding the regulatory network of mesendodermal/cardiac differentiation, but also establishes a previously uncharacterized connection between PP2A and mesendodermal specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE211235 | GEO | 2022/08/18

REPOSITORIES: GEO

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FAM122A is required for mesendodermal and cardiac differentiation of embryonic stem cells [RNA-seq]

Project description:Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved house-keeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multi facet physiological and pathological processes, however, the in vivo function of FAM122A is largely unknown. In this study, we found that Fam122 deletion results in embryonic lethality with severe defects of cardiovascular developments and significantly attenuates the cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impairs mesendodermal specification and cardiac differentiation from mouse embryonic stem cells, but not influences the pluripotent identity. Mechanical investigation shows that the impaired differentiation potential is caused through the dysregulation of histone modification and Wnt and Hippo signaling pathways by modulating PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This not only significantly extends our understanding the regulatory network of mesendodermal/cardiac differentiation, but also establishes a previously uncharacterized connection between PP2A and mesendodermal specification.

2022-08-18 | GSE211234 | GEO

CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

Project description:While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A confers cellular resistance to CHK1 inhibitors and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase which dephosphorylates the WEE1 protein and rescues WEE1 from Ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1 inhibitors. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1 inhibitor plus a WEE1 inhibitor can overcome CHK1 inhibitor resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1 inhibitor sensitivity or resistance.

2021-01-01 | GSE158338 | GEO

Transcriptomics analysis of FAM122A knockout and NC K562 cells

Project description:To understand the molecular mechanism associated with increased erythroid differentiation upon FAM122A deletion, we performed RNA sequencing to examine the global gene expression profiling of FAM122A KO and NC K562 cells.

2020-07-30 | GSE141735 | GEO

Cell Fusion Enhances Mesendodermal Differentiation of Human Induced Pluripotent Stem Cells.

Project description:Human induced pluripotent stem cells (iPS cells) resemble embryonic stem cells and can differentiate into cell derivatives of all three germ layers. However, frequently the differentiation efficiency of iPS cells into some lineages is rather poor. Here, we found that fusion of iPS cells with human hematopoietic stem cells (HSC) enhances iPS cell differentiation. Such iPS hybrids showed a prominent differentiation bias towards hematopoietic lineages but also towards other mesendodermal lineages. Additionally, during differentiation of iPS hybrids expression of early mesendodermal markers - Brachyury (T), MIX1 Homeobox-Like Protein 1 (MIXL1) and Goosecoid (GSC) - appeared with faster kinetics than in parental iPS cells. Following iPS hybrid differentiation there was a prominent induction of NODAL and inhibition of NODAL signaling blunted mesendodermal differentiation. This indicates that NODAL signaling is critically involved in mesendodermal bias of iPS hybrid differentiation. In summary, we demonstrate that iPS cell fusion with HSC prominently enhances iPS differentiation. 11 samples were hybridized GeneChip Human Gene 1.0 ST Arrays (Affymetrix)

2014-08-06 | E-GEOD-58457 | biostudies-arrayexpress

Identification of Fam122a regulated genes in LT-HSCs.

Project description:We report differences in gene expression between WT and Fam122a KO LT-HSCs.

2020-05-28 | GSE151261 | GEO

Cell Fusion Enhances Mesendodermal Differentiation of Human Induced Pluripotent Stem Cells

2014-08-06 | GSE58457 | GEO

Nodal signaling maintains H3K18ac landscape to promote mesendodermal differentiation through TRIM33

Project description:The epigenome of a cell is established and maintained by chromatin modifiers and remodelers, which are recruited to the chromatin by specific transcription factors. In this report, we show that nodal cross-talks with the epigenome through TRIM33-H3K18ac to mediate mesendodermal genes expression. The chromatin accessibility at mesendodermal genes depends on TRIM33. Moreover, histone acetylation is essential for TRIM33 recruitment to many nodal target genes involved in mesendodermal differentiation. The distribution pattern of the H3K18ac mark changes from foci to expanded domains at the mesendodermal genes promoter during embryonic stem cells (ESCs) differentiation to embryoid bodies (EBs). This could be the cue to facilitate TRIM33 colocalized with Smad2/3 at chromatin in EBs but not in ESCs. TRIM33 interacts with the H3K18ac “writer” p300 dependent on nodal signaling, providing a positive feedback to promote activation of mesendodermal genes and association with HDAC1 plays a negative role in activation of mesendodermal genes.

2019-06-01 | GSE115169 | GEO

Whsc1 controls mesendodermal transcription factor expression

Project description:We report here chromatin related factor Whsc1 links pluripotency exit and mesendodermal differentiation. We performed RNA-seqs to compare Whsc1+/+ and Whsc1-/- embryonic stem cells (ESCs) to compare the transcriptomes. UMI-4C experiments have been performed to identify regions having contacts with promoter regions of downstream Whsc1 targets: the mesendoderm transcritpion factors

2019-06-20 | GSE126618 | GEO

Bach1 Regulates the Self-renewal and Mesendodermal Differentiation of Human Embryonic Stem Cells

Project description:Transcription factor Bach1 is a member of the alkaline leucine zipper protein family. Our results therefore highlight a critical role for Bach1 proteins in a regulatory network that integrates essential Wnt/β-catenin and nodal-Smad signaling to repress mesendodermal differentiation of pluripotent cells

2019-03-28 | GSE113817 | GEO

Modulation of the bulk cell density as decisive parameter and simple method for mesendodermal patterning of human pluripotent stem cells

Project description:1 million human pluripotent cells cultured as suspension aggregates (hES3-NKX2.5 cell line) were treated with 0, 7.5 or 15µM CHIR99021 in 1 or 3 ml RPMI/B27 (w/o insulin) for 24h to induce the differentiation of human pluripotent stem cells (hPSCs). CHIR99021 is a potent GSK3 inhibitor that results in prominent WNT pathway activation and thereby induces mesendodermal differentiation.

2016-12-30 | E-MTAB-5051 | biostudies-arrayexpress

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