A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle

Miao, Zhi Feng; Lewis, Mark A.; Cho, Charles J.; Adkins-Threats, Mahliyah; Park, Dongkook; Brown, Jeffrey W.; Sun, Jing; Burclaff, Joseph; Kennedy, Susan; Lü, Jianyun; Mahar, Marcus; Vietor, Ilja; Huber, Lukas A.; Davidson, Nicholas O.; Cavalli, Valeria; Rubin, Deborah C.; Wang, Zhenning; Mills, Jason C.

doi:10.1016/j.devcel.2020.07.005

Cited by 58 publications

(68 citation statements)

References 72 publications

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“…Here, we observe striking transcriptional overlap between metaplastic cells in the pancreas and those of the stomach. Our results are in line with recent studies indicating that mature cells like gastric chief cells and pancreatic acinar cells have a shared injury-induced plasticity program, paligenosis, that governs their conversion from the differentiated to regenerative states 3, 25, 57 . Cycles of paligenosis that fuel pyloric metaplasia may allow cells to accumulate mutations and increase the risk for progression to cancer.…”

Section: Discussionsupporting

confidence: 92%

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from genetically wild type ADM, the associated transcriptional changes, and to identify markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Single-cell trajectories were generated. Data were compared to gastric metaplasia and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population (Muc6+, Tff2+) resembling gastric pyloric, gland-base cells. Lineage trajectories suggest that this pyloric metaplasia is an intermediate cell identity between acinar cells and the generation of metaplastic tuft and enteroendocrine cells (EECs). 3-D electron microscopy demonstrates that all identified lineages populate ADM lesions. EECs exhibit substantial heterogeneity, including emergence of enterochromaffin (5-HT+) and delta (SST+) cells. Human pancreatitis shows a similar pyloric metaplasia phenotype and a conserved transcriptional program. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo pyloric metaplasia to mucinous progenitor-like populations, some of which can then seed disparate tuft cell and EEC lineages. EEC subtypes are diverse with the potential to direct disease progression. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases. Keywords: plasticity, pancreatitis, paligenosis, SPEM, Tuft cells, Enteroendocrine cells

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Section: Discussionsupporting

confidence: 92%

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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“…ATF3 was previously characterized in the early stages of cerulein‐induced pancreatitis in mice (Fazio et al , 2017; Data ref: Fazio et al , 2017) and our in silico ‐predicted ATF3‐binding site matched a site from chromatin immunoprecipitation sequencing (ChIP‐Seq) analysis of genomic ATF3 binding early after cerulein injury from the published dataset (Fig EV3A–C). ATF3 was also an appealing target because it was previously described as one of the most highly upregulated genes in a mouse model of SPEM (Nozaki et al , 2008; Miao et al , 2020b). Thus, the data pointed to ATF3 as a key transcription factor early in paligenosis, potentially activating Rab7 to facilitate the massive autophagic changes in Stage 1.…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that two genes meeting those criteria are Ddit4 (mentioned above) and Ifrd1 . DDIT4 is invoked early in paligenosis to quench mTORC1, which must be shut off for the massive autophagy and lysosomal activity of Stage 1, while IFRD1 is essential to restore mTORC1 activity for entry into S phase (Miao et al , 2020b).…”

Section: Introductionmentioning

confidence: 99%

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

et al. 2021

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Differentiated cells across multiple species and organs can re‐enter the cell cycle to aid in injury‐induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive‐enzyme‐secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3–/– mice fail to induce RAB7‐positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.

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“…This occurs in response to various hormonal signals [ 172 ]. It is not clear whether the autophagy induced during reprogramming is under the control of TOR in plants, although cellular dedifferentiation followed by reactivation of cell proliferation in animals after wounding is controlled by the level of TOR activity, providing a precedent for a role for TOR also in plant cell reprogramming [ 173 ].…”

Section: Tor Signaling In Photosynthetic Organismsmentioning

confidence: 99%

Target of Rapamycin in Control of Autophagy: Puppet Master and Signal Integrator

Mugume

Kazibwe

Bassham

2020

IJMS

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The target of rapamycin (TOR) is an evolutionarily-conserved serine/threonine kinase that senses and integrates signals from the environment to coordinate developmental and metabolic processes. TOR senses nutrients, hormones, metabolites, and stress signals to promote cell and organ growth when conditions are favorable. However, TOR is inhibited when conditions are unfavorable, promoting catabolic processes such as autophagy. Autophagy is a macromolecular degradation pathway by which cells degrade and recycle cytoplasmic materials. TOR negatively regulates autophagy through phosphorylation of ATG13, preventing activation of the autophagy-initiating ATG1-ATG13 kinase complex. Here we review TOR complex composition and function in photosynthetic and non-photosynthetic organisms. We also review recent developments in the identification of upstream TOR activators and downstream effectors of TOR. Finally, we discuss recent developments in our understanding of the regulation of autophagy by TOR in photosynthetic organisms.

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A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle

Cited by 58 publications

References 72 publications

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

Target of Rapamycin in Control of Autophagy: Puppet Master and Signal Integrator

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