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Abstract
The inability of differentiated cells to maintain their identity is a hallmark of age-related diseases. We found that the transcription factor Hey supervises the identity of differentiated enterocytes (ECs) in the adult Drosophila midgut. Lineage tracing established that Hey-deficient ECs are unable to maintain their unique nuclear organization and identity. To supervise cell identity, Hey determines the expression of nuclear lamins, switching from a stem-cell lamin configuration to a differentiated lamin configuration. Moreover, continued Hey expression is required to conserve large-scale nuclear organization. During aging, Hey levels decline, and EC identity and gut homeostasis are impaired, including pathological reprograming and compromised gut integrity. These phenotypes are highly similar to those observed upon acute targeting of Hey or perturbation of lamin expression in ECs in young adults. Indeed, aging phenotypes were suppressed by continued expression of Hey in ECs, suggesting that a Hey-lamin network safeguards nuclear organization and differentiated cell identity.
Highlights
Using MyoIAts-GAL4, driving the expression of UAS-LamDm0 we identified 810 differentially expressed genes (DEG) upon LamDm0 expression in ECs compared with control (UAS-GFP, PCA analysis shown in Figure 5—figure supplement 4, and see Materials and methods)
We identified Hey, but not other HES transcription factors, as a critical supervisor of EC identity and suggest the following working model (Figure 7M): Hey regulates EC identity in part by establishing and sustaining a transcriptional switch in the expression of nuclear lamins
Hey promotes the expression of EC gene signatures, including Pdm1 and lamin C (LamC), the latter inhibits the expression of stem cell- and non-gutrelated genes in ECs
Summary
Experiments such as nuclear transfer and reprogramming of differentiated fibroblasts into pluripotent cells (iPS) have changed the classical view of a rigid ‘terminally-differentiated’ cell state to a more plastic one (Gurdon, 1962; Takahashi and Yamanaka, 2006; Morris, 2016), suggesting that once established, differentiated cells must actively maintain their identities (Blau and Baltimore, 1991; Natoli, 2010; Holmberg and Perlmann, 2012; Bitman-Lotan and Orian, 2018). Recently it was shown that loss of identity is a hallmark of the aging Drosophila midgut (Li et al, 2016) Differentiated cells maintain their identity by multiple mechanisms, including tissue-specific transcription factors (TFs) and the control of high-order chromatin structure (e.g., Cobaleda et al, 2007; Natoli, 2010; Holmberg and Perlmann, 2012; Lin and Murre, 2013). Nuclear lamins are essential in establishing a nuclear organization that is unique to the differentiated state (Kohwi et al, 2013; Gruenbaum and Foisner, 2015) These mechanisms likely serve as a barrier against pathological reprograming and are highly relevant to human disease and regenerative medicine. While differentiated cells exhibit distinct chromatin and nuclear organization, the mechanisms
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