In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as ; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.
We hypothesized that basic helix-loop-helix (bHLH) MIST1 (BHLHA15) is a "scaling factor" that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autophagosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural "blueprints."
Essentially all cells contain a variety of spatially restricted regions that are important for carrying out specialized functions. Often, these regions contain specialized transcriptomes that facilitate these functions by providing transcripts for localized translation. These transcripts play a functional role in maintaining cell physiology by enabling a quick response to changes in the cellular environment. Here, we review how RNA molecules are trafficked within cells, with a focus on the subcellular locations to which they are trafficked, mechanisms that regulate their transport and clinical disorders associated with misregulation of the process. K E Y W O R D SRNA binding protein, RNA cis-element, RNA localization, RNA transport, zipcode
Thousands of RNA species display nonuniform distribution within cells. However, quantification of the spatial patterns adopted by individual RNAs remains difficult, in part by a lack of quantitative tools for subcellular transcriptome analysis. In this study, we describe an RNA proximity labeling method that facilitates the quantification of subcellular RNA populations with high spatial specificity. This method, termed Halo-seq, pairs a light-activatable, radical generating small molecule with highly efficient Click chemistry to efficiently label and purify spatially defined RNA samples. We compared Halo-seq with previously reported similar methods and found that Halo-seq displayed a higher efficiency of RNA labeling, indicating that it is well suited to the investigation of small, precisely localized RNA populations. We then used Halo-seq to quantify nuclear, nucleolar and cytoplasmic transcriptomes, characterize their dynamic nature following perturbation, and identify RNA sequence features associated with their composition. Specifically, we found that RNAs containing AU-rich elements are relatively enriched in the nucleus. This enrichment becomes stronger upon treatment with the nuclear export inhibitor leptomycin B, both expanding the role of HuR in RNA export and generating a comprehensive set of transcripts whose export from the nucleus depends on HuR.
The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4␣ (HNF4␣) directly induces XBP1 expression. Mutations in HNF4␣ cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human-disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4␣ caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca 2؉ signaling; we show that diminished XBP1 and/or HNF4␣ in -cells led to impaired ER Ca 2؉ homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4␣-deficient -cells. Our findings uncover a transcriptional relationship between HNF4␣ and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.Cells use transcription factors to regulate expression of gene cohorts that coordinate response to stress, determine specific developmental fates, and scale intracellular architecture during development and disease(1, 2). When the biosynthetic load of a cell is increased and misfolded proteins accumulate in the endoplasmic reticulum (ER), 2 the volume and composition of the ER is altered to facilitate the synthesis and processing of nascent polypeptides via the unfolded protein response (UPR) pathway. One of the principal components of the UPR is the transcription factor X-box-binding protein 1 (XBP1), which is canonically activated via IRE1 splicing of the XBP1 transcript during ER stress (3, 4). However, XBP1 also establishes and maintains the subcellular machinery for synthesizing large quantities of protein during the normal development of professional secretory cells (2, 5). While the majority of genes activated by XBP1 are involved in ER biogenesis, up to 40% of its targets are not directly linked to the ER-stress response (6), further supporting its functions outside the UPR. In addition, the increased XBP1 that coordinates the scaling up of the secretory apparatus during development and homeostasis of dedicated secretory cells does not seem to require activation of the UPR (7). How XBP1 is induced and maintained during differentiation of secretory cells even in the absence of substantial ER stress is unclear, but a potential alternative mechanism is that Xbp1 may also be transcriptionally regulated. Hepatocyte Nuclear Factor 4-alpha (HNF4␣) is a highly conserved transcription factor responsible for orchestrating the early development and maintenance of multiple adult organs. As a master developmental regulator, HNF4␣ likely acts upstream of the factors that establish the extensive cellular machinery required in professional secretory cell lineages within those organs. Despite overlapping expression and function, no direct relationship between HNF4␣ and Xbp1 h...
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