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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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Project description:The Ser/Thr protein phosphatase 2A (PP2A) is a highly conserved collection of heterotrimeric holoenzymes responsible for the dephosphorylation of many regulated phosphoproteins. Substrate recognition and the integration of regulatory cues are mediated by B regulatory subunits that are complexed to the catalytic subunit (C) by a scaffold protein (A). PP2A/B55 substrate recruitment was thought to be mediated by charge-charge interactions between the surface of B55a and its substrates. Challenging this view, we recently discovered a conserved SLiM [RK]-V-x-x-[VI]-R in a range of proteins, including substrates such as the retinoblastoma-related protein p107 and TAU (Fowle et al. eLife 2021;10:e63181). Here we report the identification of this SLiM in FAM122A, an inhibitor of B55a/PP2A. This conserved SLiM is necessary for FAM122A binding to B55a in vitro and in cells. Computational structure prediction with AlphaFold-Multimer predicts an interaction consistent with the mutational and biochemical data and supports a mechanism whereby FAM122A uses the 'SLiM' in the form of a short a-helix (helix 1) to dock to the B55a top groove, thereby blocking substrate binding to the same site. In this model, FAM122A also spatially constrains substrate access by occluding the catalytic subunit with a second a-helix immediately adjacent to helix 1. Consistently, FAM122A functions as a competitive inhibitor as it prevents the binding of substrates in in vitro competition assays and the dephosphorylation of CDK substrates by B55a/PP2A in cell lysates. The ablation of FAM122A in human cell lines reduces the rate of proliferation, progression through cell cycle transitions, and abrogates G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells results in attenuation of CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a short helical motif (SHeM)-dependent, substrate-competitive inhibitor of B55a/PP2A that suppresses multiple functions of B55a in the DNA damage response and in timely progression through the cell cycle interphase.

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

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