REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

Rovira, Meritxell; Atla, Goutham; Maestro, Miguel A.; Grau, Vanessa; Hurtado, J. Garcia; Maqueda, María; Mosquera, José Luis; Kerr–Conte, Julie; Pattou, François; Ferrer, Jorge

doi:10.1101/2021.03.17.435876

Cited by 3 publications

(3 citation statements)

References 79 publications

(132 reference statements)

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“…We observed that nearly 65% of ins + cells in the secondary islets (residing along the large ducts) can be lineage traced (Figure 3E-H and Figure EV6D). Furthermore, we performed short-term lineage tracing experiments in the presence of a Notch inhibitor (LY411575) or a REST inhibitor (X5050), as previous studies described (29, 47), to demonstrate the neogenic potential of nkx6.1 + intrapancreatic ductal cells in zebrafish larvae (Figure EV5). We found that more than 80% of ins + cells and around 75% of gcg + cells in the pancreatic tail can be lineage traced after three-day treatment (3-6 dpf) with LY411575 and X5050, respectively.…”

Section: Resultsmentioning

confidence: 99%

Efficient knock-in method enabling lineage tracing in zebrafish

Andersson

2022

Preprint

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The CRISPR-Cas9 system aids generation of knock-in zebrafish lines, but it has been hard to integrate large constructs and avoid disrupting the targeted genes. Here we devised a 3' knock-in strategy of PCR-amplified dsDNA, which coded for fluorescence proteins and Cre recombinase in frame with the endogenous gene but separated from each other by self-cleavable peptides. Primers with 5' AmC6 end-protections generated improved PCR amplicons harboring either short or long homologous arms, which were co-injected with pre-assembled Cas9/gRNA ribonucleoprotein complexes for early integration. We targeted four genetic loci (krt92, nkx6.1, krt4, and id2a) and generated ten knock-in lines, which function as reporters for the endogenous gene expression. The knocked-in iCre or CreERT2 were used for lineage tracing, which suggested nkx6.1+ cells are multipotent pancreatic progenitors that gradually restrict to bipotent duct; while id2a+ cells are multipotent in both liver and pancreas and gradually restrict to ductal cells. Additionally, hepatic id2a+ duct show progenitor properties upon extreme hepatocyte loss. Thus, we present an efficient knock-in technique with widespread use for both cellular labelling and lineage tracing.

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Section: Resultsmentioning

confidence: 99%

Efficient knock-in method enabling lineage tracing in zebrafish

Andersson

2022

Preprint

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“…Rest is a master regulator of neurogenesis and has been previously described to inhibit direct reprogramming of pancreatic exocrine to endocrine cells by inhibiting the binding of Pdx1 to key endocrine differentiation-related genes [59]. In addition, loss of Rest results in increased generation of pancreatic endocrine cells during development [60, 61]. Nfib belongs to the Nuclear Factor I protein family, of which another member, Nfia , plays a role in the induction of EP cell fate [62].…”

Section: Resultsmentioning

confidence: 99%

Single-cell chromatin accessibility of developing murine pancreas identifies cell state-specific gene regulatory programs

Liu

Chang

et al. 2022

Preprint

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Numerous studies have characterized the existence of cell subtypes, along with their corresponding transcriptional profiles, within the developing mouse pancreas. The upstream mechanisms that initiate and maintain gene expression programs across cell states, however, remain largely unknown. Here, we generate single-nucleus ATAC-Sequencing data of developing murine pancreas and perform an integrated, multi-omic analysis of both chromatin accessibility and RNA expression to describe the chromatin landscape of both the developing epithelium and mesenchyme at E14.5 at single-cell resolution. We identify candidate transcription factors regulating cell fate and construct gene regulatory networks of active transcription factor binding to regulatory regions of downstream target genes. This work serves as a valuable resource for the field of pancreatic biology in general and contributes to our understanding of lineage plasticity among endocrine cell types. In addition, these data identify which epigenetic states should be represented in the differentiation of stem cells to the pancreatic beta cell fate in order to best recapitulate in vitro the gene regulatory networks that are critical for progression along the beta cell lineage in vivo.

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“…Pancreatic beta cells and neuronal cells share similar functions. Repressor element-1 silencing transcription factor (Rest) is important for the terminal differentiation of pancreatic beta cells and neuronal cells through the regulation of neuronal and pancreatic endocrine gene 1 2 3 4 5 . Generally, the Rest gene is not expressed in mature pancreatic beta cells and beta cell line 6 and is classified as a disallowed gene in pancreatic beta cells 7 .…”

Section: Introductionmentioning

confidence: 99%

Aberrant Expression of Rest4 Gene in Low-Functioning Pancreatic Beta Cell Line

Yamato

2023

Horm Metab Res

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Repressor element-1 silencing transcription factor (Rest) is not expressed in pancreatic beta cells and neuronal cells. However, Rest4, a truncated form of Rest, is expressed in high passaged MIN6 (HP-MIN6) cells, a pancreatic beta cell line that lost glucose-responsive insulin secretion. Rest4 is also expressed in injured MIN6 cells and isolated islets. Herein, the forced expression of dominant negative form of Rest in HP-MIN6 cells was subjected to microarray analysis of gene expression to investigate the role of Rest4 gene in MIN6 cells. Furthermore, the forced expression of Rest4 gene in MIN6 cells was subjected to microarray analysis of gene expression to investigate the function of Rest4 in normal insulin-producing cells. The results showed that Rest4 inhibits cell proliferation and DNA and RNA metabolism, and stimulates secretory mechanisms and nervous system gene expression. These findings suggest that Rest4 may act defensively against cellular injury in pancreatic beta cells.

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REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

Cited by 3 publications

References 79 publications

Efficient knock-in method enabling lineage tracing in zebrafish

Efficient knock-in method enabling lineage tracing in zebrafish

Single-cell chromatin accessibility of developing murine pancreas identifies cell state-specific gene regulatory programs

Aberrant Expression of Rest4 Gene in Low-Functioning Pancreatic Beta Cell Line

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